It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

This funding opportunity announcement (FOA) encourages Cooperative Agreement (U54) applications from institutions/organizations for Pilot Centers for Precision Disease Modeling which will establish pipelines for preclinical scientific discovery, disease modeling and development of clinical interventions based on innovative animal models. These pipelines eventually will be integrated into diagnostics, care and therapeutic treatment of human patients. The goal of the program is to support collaborative research projects that link current personalized medicine efforts in humans with advances in animal genomics and technologies for genetic manipulation to enhance the predictive value of preclinical studies. Optimization of this collaborative effort may be accomplished by linking existing programs within a single institution and/or by reaching across multiple institutions. This program will support a limited number of Centers that will function as focal points to define, test, and use the principles, knowledge, and expertise needed to address the unique requirements of individual patients or groups of patients. The Centers will start working on several demonstration projects and then will focus on high-throughput projects, which will be nominated by the research community on local, regional and national bases and selected by each Center’s Steering Committee. It is expected that a specific Center will maintain multifaceted research activities to build and study model systems that can be adjusted as required to accommodate a broad spectrum of diseases. Applications to develop animal models that relate strictly to a specific disease or category of research will not be considered for funding. For example, applications from investigators interested in models or model systems with a primary focus on heart disease, neurological disorders or cancer would not be considered acceptable. Furthermore, ORIP only supports studies that are related to the interests of multiple NIH Institutes and Centers. Applications proposing studies that are related predominantly to the interest of one NIH Institute or Center (IC) and only peripherally to the interests of other ICs will be withdrawn.. Resources created by the Centers and related services will be provided to the biomedical community. Each Center should have a set of required components, including a Preclinical/Co-Clinical Section, which will be responsible for the collection of patient-specific information and will facilitate reciprocal interactions with clinical studies, conducted elsewhere. This approach recognizes a number of critical needs: an effective collaboration between clinical and research studies; a centralized service to process medical, genetic and other omics information; improved phenotype-disease ontologies; comparative medicine research; creation of genetically/somatically modified animal models in the most appropriate species; and the ability to test the predictive validity of newly created disease models in preclinical applications.

Background

Recent advances in diverse areas of biomedical science and breakthroughs in technology such as affordable whole genome sequencing and molecular profiling (epigenomic, transcriptomic, proteomic and metabolomic) provide a unique opportunity to study the genetics and pathogenesis of a wide variety of human diseases with the eventual goal of using this information to treat patients according to their specific genetic composition and molecular phenotype. Heterogeneity of patient populations and the absence of effective means to interpret patient genetic/omic information for clinical use are significant obstacles toward achieving this goal. Creating optimally informative animal models to generate reliable preclinical data for human studies is a fundamental aspect of this challenge.

Preclinical animal studies and their translation are usually large, expensive and multidisciplinary projects, requiring extensive use, storage and interpretation of patient-specific information and analysis of human and animal genetic/omics databases, which can relate human diseases to animal model phenotypes. These studies also involve complex manipulation of animal genetics or creation of somatic hybrids and interpretation of research results involving a variety of treatment modalities in animals and humans. Among other obstacles are limited access by individual investigators to the high-throughput approaches needed for testing gene function in different genetic contexts, often necessary for comprehensive functional annotation of variants; disease modeling and therapeutic screening; lack of disease allele collections in relevant model species; and guiding principles to choose the best model system for a particular application. The ability to produce animals with specific genetic modifications and to replace specific cells and tissues in a variety of species has recently been enhanced dramatically by the development of new technologies, such as nuclease-mediated genome editing and isolation, characterization and modification of induced pluripotent stem cells. These advances will help investigators create animals with phenotypes more closely analogous to those of human patients cost-effectively in a relatively short period of time.

Examples of these next generation animal models in an early stage of development include personalized immune mouse transplantation models for autoimmune diseases, specialized rodent cohorts in co-clinical cancer drug treatment trials, and animals with reconstructed microbiomes for modeling host-gene-metagenome interactions, novel treatment approaches for cancer patients based upon personalized Drosophila models as a whole-animal screening platform. There is an urgent need to apply and enlarge on these types of approaches by supporting research projects that will provide a variety of animal models, including non-rodent species, to examine the causal relationships of genetics and omic information to human biology and disease, to validate disease-associated genetic variations and biomarkers, to reduce drug candidate attrition, and to develop new types of individualized therapies for monogenic and complex disorders. The Division of Comparative Medicine/ORIP/DPCPSI/OD/NIH convened a symposium on October 28 29, 2013 in Bethesda, Maryland that evaluated the potential use of personalized animal models across the phylogenetic spectrum for translational medicine applications (see http://dpcpsi.nih.gov/sites/default/files/Animal_Models_and_Personalized_Medicine_Meeting_Summary.pdf). The results of this symposium and the recommendations of the biomedical community provide the basis for previous FOA issued in 2014 and this FOA.

Research Objectives

Projects supported by ORIP under this FOA are intended to provide funding for research centers that will evaluate the predictive value of preclinical studies based on the use of a new generation of precision animal models, thus eventually providing guidance for subsequent clinical applications, including advanced diagnostics, novel therapeutics, clinical trials, etc.

Precision animal models can be used for investigations of disease mechanisms; target identification and validation; development of diagnostics, biomarkers and new drugs; and testing and optimization of therapies. The Centers described in this FOA are not intended to accelerate implementation of already known information or to incrementally refine existing models, rather for creating precision animal models to advance our understanding of disease mechanisms and causes, discover new research paradigms and create new opportunities to connect patient-specific disease processes with innovative treatment options. The individual Centers, which may be multi-institutional, must have a Coordination Section, Preclinical/Co-Clinical Section, Bioinformatics Section, Resource and Service Section and Disease Modeling Unit. The proposed cooperative agreements will develop the sections and unit, which will be integrated in a functional pipeline open for use by broad biomedical community. This pipeline will help to overcome major bottlenecks between diagnosing human diseases, understanding disease mechanisms and predicting the therapeutic responsiveness of new treatments using precision animal models.

The objectives of the Pilot Centers for the Disease Modeling program include, but are not limited to:

• Improving methods to rapidly model disease-specific genomic alterations, including robust phenotyping to assess if specific genetic changes recapitulate a human phenotype. Combining phenotyping assays with detailed molecular analysis (omics profiling) should be sufficiently integrative to assist interpretation of disease processes shared in model organisms and human patients. Of specific interest are studies aimed at understanding the functional significance of different coding and non-coding variants and their risk assessment. Creating animal model systems that have the potential to be used in preclinical applications (such as standardized and rigorous safety, toxicity and efficacy testing as well as independent validation of efficacy) leading to substantial benefits for the target patient population and in clinical decision-making with a direct impact on patient management.
• Creating new and improved disease taxonomy and phenotype ontologies to better assist translation of specific patient information to the most appropriate animal model systems and disease categories. Developing an efficient validation process for incorporating animal model data into a knowledge network related to a specific disease and a new taxonomy.
• Accelerating testing of new targeted therapies using animal models.
• Stratifying potential patient responses on the basis of genetic/omics criteria.
• Developing combinatorial treatments.
• Repurposing drugs and optimizing treatments for rare orphan diseases.
• Discovering and developing predictive, reliable biomarkers across species, including humans. Development of biomarkers usable both in animals and humans will significantly increase translatability of animal models. Cross-validation of animal model end-points with clinical measures in humans will be critical. Comprehensive biomarker analysis may be centered, for example, on high-throughput genomic and gene expression platforms as well as other omics. The eventual goal is to aid future clinical applications in disease prediction, prognosis, patient selection, dosing and monitoring.
• Developing a co-clinical program that will standardize protocols for animals and humans, which should closely match each other in terms of both data acquisition and data analysis, and be efficiently communicated among basic, clinical and pharmaceutical researchers. It is also desirable to have access to existing human/animal comparative pathology and imaging centers. This will require developing pathology technologies and resources to support disease phenotyping efforts as well as preclinical studies. Data collection and management must be organized to permit access and integration within the Center.
• Developing systematic approaches to functional genomic validation of potential causes of disease and markers of therapy response/sensitivity, which along with the use of the model organisms can include cell-based models. Providing a foundation for the development of drugs and therapeutics tailored to specific genetic profiles.
• Projects that go beyond testing of a limited number of genomic variants, but rather evaluate large-scale genomic data using a variety of high-throughput technologies are highly encouraged.

Centers, being NIH-funded centralized resources, should provide development plans for wide access and use by the research and medical communities in diverse fields of diagnostics, new therapeutics and effective preventive medicine strategies. This includes a mechanism for outreach and awareness to the broader research community, and deposition of data and models in a publicly accessible repository system. Leveraging available institutional support and other resources and identifying a clear path to sustainability of the successful implementation project are strongly encouraged.

Organization of Individual Pilot Centers for Precision Disease Modeling

Organization: Each Pilot Center for Precision Disease Modeling will consist of a transdisciplinary research team of investigators with complementary expertise organized around a scientific framework to address specific medical problem(s) by creating and studying precision animal models.

Each Center will consist of the following sections and unit:

• The Coordination Section will manage and coordinate Center research and other activities, and will have oversight for sharing within the Center all sets of data generated by each of the other section(s) and units consistent with achieving the goals of the program. This Section should develop a plan for outreach and recruitment of the community-based nominations of the human allele variants for the generation of precision animal models. This plan will be guided by collaborations with researchers and clinicians for known or suspected novel disease conditions that collectively exhibit a wide range of clinically and biologically informative phenotypes. The Coordination Section, with help from the Bioinformatics Section, will develop an active program for monitoring and collecting information on the impact of the Center’s ongoing activities on biomedical research. Such information should also be included in the Center s progress reports to the NIH.
• The Preclinical/Co-Clinical Section will be responsible for clinical interactions, such as collection of patient genomic and other omics information, previously generated through clinical or research testing and medical records, and will be critical for determining the research focus of the projects on translation of basic research discoveries via precision animal models to applications in human patients. For the purpose of this FOA, the term co-clinical relates to investigations using animal models that are conducted in parallel with human clinical trials. The preclinical animal-based experiments should be conducted in appropriate genetically-modified animals in which the relevant clinical, biological, and pharmacologic information (i.e., somatic mutational background, germline single nucleotide polymorphism variations, responsiveness to specific regimens, imaging, microarray, and proteomics profiles) are accrued and analyzed in parallel with studies performed with human patients. The parallel animal and human studies should be integrated to predict responses to specific treatments. Funding under the auspices of this FOA cannot be requested for the human clinical trial component of these co-clinical investigations. This section will be responsible for the information exchange with other Sections to evaluate the quality of newly created animal models and validation of the use of animal models for specific preclinical applications.
• The Bioinformatics Section will create and maintain the Center website and conduct cutting-edge computational research activities to support decision-making processes regarding selection of specific genetic alleles or variations to model in a particular animal species as well as predicting possible outcomes of the genetic/cell interventions and expected phenotypic features. An important function of this Section will be collecting data from the animal model generation process; genotyping and phenotyping; sharing the information with the larger biomedical community, especially clinical users; and evaluating the impact of the Center s activities. This Section will assist the Resource and Service Section with maintaining the catalog of generated animal strains and biomaterials and communicating with customers.
• The Resource and Service Section will acquire mutant animal strains and other biomaterials from the Disease Modeling Section; evaluate, achieve, and breed animals and distribute resources generated by the Center; and provide unique services developed by the Center on a fee-for-service basis to the wider biomedical community. Animal strains and biomaterials should be held to the highest standards to optimize reproducibility of studies and assure scientific rigor and transparency; all strains should be thoroughly characterized and documented and include additional quality control measures.
• The Disease Modeling Unit will develop projects that create and test precision animal models. This Unit should have sufficient expertise to use state-of-art contemporary approaches for genome editing and tissue transplantation appropriate to the particular animal species being used, with the objective of generating superior models for understanding disease etiology, developing and characterizing biomarkers, identifying and validating drug targets and predicting human responses to therapies.

It is expected that U54 cooperative agreements will generate Program Income by distributing the models and biomaterials, offering their production and services for a fee and recovering a certain percentage of their operating cost. Costs specifically associated with the establishment, improvement, or expansion of animal or material distributions and long-term resource maintenance should be recovered from user fees through a charge schedule acceptable to the NIH. Significant growth of Pilot Centers for Precision Disease Modeling should result from Program Income and not from an ever-increasing U54 award. Note that the Center’s use of Program Income is governed by the NIH Grants Uniform Guidance.

Steering Committee: Each Pilot Center should have a Steering Committee which will serve as the operational governing board. The Steering Committee should include: the PD(s)/PI(s), Section leads, the NIH Project Scientist (voting), the NIH Program Official (ex officio) and external scientists(s) (if required). Key co-investigators and pre- and postdoctoral trainees, in addition to the PD(s)/PI(s), are eligible to attend Steering Committee meetings (not voting). An important function of the Steering Committee will be oversight of the research projects for the Center pipeline, such as selection of variants for the analysis in model organisms, which may involve genes of unknown significance, variants of unknown significance in known causative genes or potential cases of phenotypic expansion.

External Advisory Board: An external advisory board should be organized from experts outside of the Center (the required expertise of the members should be stated, but names of the candidates should not be listed) to guide the Center leadership in assessing progress and scientific opportunities and to evaluate the progress and the effectiveness of interaction among participants.

See Section VIII. Other Information for award authorities and regulations.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core (Use for Coordination Section)	6
Core (Use for Preclinical/Co-Clinical Section, Bioinformatics Section and Resource and Service Section)	6
Project (Use for Disease Modeling Unit)	12

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required (one maximum)
• Coordination Section: required (one maximum)
• Preclinical/Co-Clinical Section: required (one maximum)
• Bioinformatics Section: required (one maximum)
• Resource and Service Center: required (one maximum)
• Disease Modeling Unit: required (one maximum)

When preparing your application, use Component Type Overall .

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete entire form.

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Follow standard instructions.

Other Attachments: The following must be submitted as a PDF attachment.

Center Organization: A diagram must be made with the organizational structure, leadership and interactions between cores and research projects. This should reflect major decision points and demonstrate collaborative nature of the center. Submit as PDF entitled Center Organization.

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

Specific Aims: State concisely the goals of the proposed Center and summarize the expected outcome(s), including the impact that the results of the proposed Center will exert on the research field(s) that it supports as well as potential clinical impact for human patients. These Aims should be overarching and at a high level and distinct from the aims of the individual sections and unit.

Research Strategy:

The Center Overview should present a concise overall vision and plan for the proposed Center. This section should describe the framework for the Center, overall experimental strategy and how it will address the objectives of the program. An important mission of the Centers will be the creation and distribution of the precision animal model resources and providing services to the biomedical community. Describe how the Sections and Disease Modeling Unit will be built around specific medical problems and how cutting-edge investigations will help to design and create advanced and predictive animal models for different applications. Describe how this research will have the potential for being moved forward into clinical research and practice. Explain the synergy to be achieved by funding this research as a center and justify why the proposed projects will be conducted more effectively and efficiently as a center.

Additional items to be addressed include:

i. Describe a process by which the research community can nominate unique human genomic variants for cost effective high-throughput testing in an animal model pipeline. After validation of the expected gene editing, the Centers will establish assays to conduct comprehensive functional and phenotyping analysis to evaluate disease-causing variants. To the extent possible, the plan should also describe how the proposed solicitation strategies would enhance the chances of success of the proposed causal variant/gene discovery approaches and study designs. The plan should include measures to improve the animal model creation and validation pipeline and potential availability of additional funds from other NIH Institutes and funding agencies.

ii. Center Organization. The Overall description of the Center should explain: 1) how the components of the Center, including key personnel, will interact, and 2) why each component is essential for addressing the overall goal of the Center. There should be bi-directional exchange between the Disease Modeling Unit and Preclinical/Co-Clinical Section directly as well as via other components of the Center.

iii. Center Expertise. The Overall description should demonstrate that the Center will include the necessary expertise to support the team science environment needed to complete the proposed transdisciplinary work. Statement should be brief and avoid duplicating details of the experience and expertise that are provided in description of specific components as well as in biosketches. The Center PD/PI (contact PD/PI for applications with multiple PDs/PIs) must be a scientist with animal models creation and use experience. The leadership team must also include additional senior/key personnel with primary expertise in bioinformatics and clinical research. Applications should demonstrate plans for ongoing communication and sharing of data and resources within the Center.

iv. Disease Modeling Unit. Briefly describe several demonstration projects (at least three for the proposed Disease Modeling Unit), including its scientific integration with the proposed organizing framework and a rationale for how each project will illustrate capacities of the Center, will generate sufficient results to attract gene variant nominations from biomedical community and collaborative studies to drive the development of new knowledge based on the proposed organizing framework.

Letters of Support: An institution applying for a Pilot Center for Precision Disease Modeling should demonstrate a commitment to the Center’s success. Letter(s) of support from senior administration officials or other institutional officials from the PD(s)/PI(s)' institution(s) must be provided. The letter(s) should describe the level of institutional support for the Center including any leveraged funding or resources that may be provided by the institution(s). All letters of the support for the Overall Component should be uploaded as a single attachment.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed

All instructions in the SF424 (R&R) Application Guide must be followed.

When preparing your application, use Component Type Admin Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

Enter Human Embryonic Stem Cells in each relevant component.

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Head and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Specific Aims: Describe concisely the plans of the proposed Coordination Section for Center leadership and explain the Core Head's specific roles and responsibilities in the management of the Center. Refer to the pdf diagram requested in the Overall section of the application.

Research Strategy: The Coordination Section will provide multidisciplinary scientific leadership for the Center by PDs/PIs, who will have expertise in a particular area of research activities. This Section will effectively coordinate interactions and collaboration of projects, cores and investigators as well as coordinate activities with the ORIP/DPCPSI/OD/NIH Program Official. The application should clearly define the management plan for the proposed Section, and how it will support achievement of the proposed goals and milestones. Describe the Coordination Section plan for the outreach and recruitment of the community-based nominations of the human allele variants for the generation of precision animal models. This plan will be guided by collaborations with researchers and clinicians for known or suspected novel disease conditions that collectively exhibit a wide range of clinically and biologically informative phenotypes. The application should also describe the plans for evaluation of progress across the Center and communication strategies to manage and track progress of the multiple projects and sites that make up the Center. The Coordination Section via interactions with Bioinformatics Section should develop an active program for monitoring and collecting information on the impact of the Center’s ongoing activities on biomedical research. Such information should also be included in their progress reports to the NIH.

Describe the External Advisory Board, but should not provide names in the application or contact prior to completion of peer review. Include plans to appoint and convene this group of up to five members at least two times per year and to document its findings and recommendations as well as the Center's changes in direction or approaches made in response. This information should be included in the regular progress reports submitted to NIH. Do not provide names of potential External Advisory Board members.

The Coordination Section should coordinate participation in Center program evaluation activities, including progress reports, site visits, and provide additional communication and materials to the ORIP/DPCPSI/OD as needed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Resource Sharing Plans should only be included in the Overall component. Individual components will adhere to the overarching Resource Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Preclinical/Co-Clinical Section)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Preclinical/Co-Clinical Section)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Preclinical/Co-Clinical Section)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Preclinical/Co-Clinical Section)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Preclinical/Co-Clinical Section)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Preclinical/Co-Clinical Section)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Preclinical/Co-Clinical Section)

Specific Aims: Describe concisely the function of the proposed Preclinical/Co-Clinical Section and provide a brief description of this Section’s interactions in support of research projects.

Research Strategy: The Preclinical/Co-Clinical Section should be the key unit in providing patient clinical information (such as electronic medical records) and high quality genetic/omics data, interpreting it for the other members of the Center and formulating the medical problem requiring a precision animal model. These activities will generate testable hypotheses and link clinical information to potential comprehensive functional annotation gained in animal models. These activities should be done under the patient protection policies within the institution’s relevant regulations and guidelines. The Preclinical/Co-Clinical Section should have the capacity to collaborate with institutional clinical researchers or health-care delivery systems to leverage existing resources, to facilitate enrollment, and to collect information from patient clinical-grade samples for biological validation of variant function observed in animal models. Collaboration and coordination efforts among all research participants and consumers/patients should help establish causation and penetrance for disease variants and genes. This Section will also play a primary role in evaluation of the community-based nominations of the human allele variants for the generation of precision animal models and providing this information to the Steering Committee and the External Advisory Board.

In addition, the Research Strategy must discuss the following areas:

i. Strong supporting evidence for the importance and appropriateness of using precision animal models for specific biomedical applications from which patient(s) will potentially benefit.

Such use might include characterization of disease pathophysiology, discovery of new drug targets and biomarkers, studies of pharmacodynamic/pharmacokinetic relationships of treatments, and determination of safety margins and toxicity.

ii. Availability and quality of the patient derived clinical data and biomedical data sets (such as transcriptome, proteome, epigenome, metabolome, etc.).

iii. Approaches for the gaining access to and utilization of patient-derived specimens, if required, for example for animal humanization.

iv. Active participation in analysis of animal model discoveries for validation purposes as well as for refinement of animal models to better reflect human phenotype or responsiveness.

v. Future plans on further use of animal models leading ultimately to applications in personalized medicine.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Resource Sharing Plans should only be included in the Overall component. Individual components will adhere to the overarching Resource Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Preclinical/Co-Clinical Section)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Bioinformatics Section)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Bioinformatics Section)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Bioinformatics Section)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Bioinformatics Section)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Bioinformatics Section)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Bioinformatics Section)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Bioinformatics Section)

Specific Aims: Describe concisely the plans of the proposed Bioinformatics Section and its role in creation of precision animal models using data on patient disease-specific alleles, clinical and other omics information.

Research Strategy: The use of human genetic and genomic/other omic information will require intense and dedicated bioinformatics efforts to fully capitalize on human and animal sequencing and current bioinformatics technologies to identify critical connections between genes, phenotypes, and their functional networks. These activities should involve tight interactions with supported NIH projects such as the Monarch Initiative (https://monarchinitiative.org/). This Section will also be responsible for development of methods to track experiments, document workflows and link this information to databases. During research investigations, large amounts of data from animal models will be collected, for example gene expression, profiling, whole genome sequencing, immunohistochemical data, morphological and imaging data, biochemical analysis etc. This information should be collected, cross-referenced, analyzed, and investigated in parallel to the existing clinical data to enable a comprehensive overview and development of a hypothesis to drive research activities. This information should also enable creation of human/animal database exchange that will drive the dissemination of both electronic (data) and physical (animal models) information and facilitate seamless integration with collaborators and outreach to the research community. Data sharing between basic and translational research will be expected to expedite further functional validation of molecular aberrations and efficient implementation of biomarker-matched personalized treatment algorithms, consistent with achieving program goals. Highly organized, annotated and user-friendly databases should be used to inform the public and private industry in the creation and use of predictive animal models. For this purpose, the Bioinformatics Section should design and maintain a website.

In addition, the Research Strategy must discuss the following areas:

i. Available software infrastructure, general computational approaches and analytical methods to be used for understanding the relationships between patient unique genetic, genomic and other omic information, and disease phenotype.

ii. Plans to conduct bioinformatics analysis of data available for human sample population research including family-based linkage studies, and linkage disequilibrium, case-control and/or family-based association studies using candidate gene approaches, haplotype, high-density whole genome scanning, deep sequencing, or whole genome sequencing to identify chromosomal loci and/or genes, gene variants, and haplotypes associated with phenotype.

iii. Computational and statistical approaches that incorporate large data sets available in public or institutional databases to predict the effects of potential genetic variation(s) on the phenotype.

iv. Approaches to support research activities involving molecular characterization, and/or functional genomic, and/or omic screens of genes or gene variants identified as being associated with disease cases under investigation, including cross-species comparisons to evaluate the effects of a particular allele across model organisms.

v. Linking human and model animal phenotyping information, which will require access to the description of adequate quantitative disease states in a patient or group of patients using an advanced semantic language and disease taxonomy.

vi. Collaboration with the Disease Modeling Unit to collect, manage and upload experimental data generated during the creation and testing of animal models.

vii. Data analysis and annotation adding value to the data including building links to human disease and GWAS studies, animal model databases, and genomic resources.

viii. Plans to assist the Resource and Service Section with maintaining the catalog of generated animal strains and biomaterials and communicating with customers.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Resource Sharing Plans should only be included in the Overall component. Individual components will adhere to the overarching Resource Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Bioinformatics Section)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Resource and Service Section)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Resource and Service Section)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Resource and Service Section)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Resource and Service Section)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Resource and Service Section)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Resource and Service Section)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Resource and Service Section)

Specific Aims: Describe the Resource and Service Section plans to acquire mutant animal strains and other biomaterials from the Disease Modeling Unit; evaluate, achieve, and breed animals and distribute resources generated by the Center; and provide unique services developed by the Center on a fee-for-service basis to the wider biomedical community on a local, regional, and national basis.

Research Strategy: The applicant must propose detailed plans describing the design and development of the Resource and Service Section, including future capacities of the research resource as well as procedures for acquisition, evaluation, characterization, cryopreservation, and distribution of animal model, germ lines and related biomaterials and pathogen screening. The applicant must describe the design of quality control procedures, data collection, analysis, and verification tests. The Resource and Service Section should closely collaborate with Bioinformatics Section to design and develop databases and a free public homepage, which should provide a user-friendly accounting of the resource’s holdings. Efforts aimed at enhancing the capacity and evaluating the process of the Center to engage biomedical researchers and encourage requests for living and cryopreserved animal strains and related biomaterials should be presented.

Animal strains and biomaterials should be held to the highest standards to optimize reproducibility of studies and assure scientific rigor and transparency; all strains should be thoroughly characterized and documented and include additional quality control measures. A critical component of improving research reproducibility is to develop approaches for unique identification of research resources in public databases, including publications. The Centers should register catalogs of their resources with current resource tagging and identification initiatives, such as FORCE 11. These Centers should also work with investigators to encourage the use of Research Resource Identifiers (RRIDs) assigned by http://scicrunch.com/resources in their publications and reports.

The plan needs to provide access for biomedical researchers who have technical questions regarding the search for or specification of animal strains; who need assistance with decisions on ordering living animals, or cryopreserved germ cells; or who are looking for a specific fee-for-service. Moreover, the applicant must outline plans for future communication and submission of animal models for wider long-term distribution to NIH-supported public repositories, such as the Mutant Mouse Resource and Research Centers, Bloomington Drosophila Stock Center, Zebrafish International Resource Center, etc.

In addition, the Research Strategy must discuss the following areas:

i. The management plan for the proposed project, and how it will support achievement of the proposed goals and milestones. The application should describe the organization of the proposed Center effort, and its management structure, including the integration of the separate components to form an efficient pipeline to acquire, evaluate, cryopreserve, and distribute high-quality mutant animals to a requesting investigator. The plan should include reporting relationships of the key personnel. The plan should also describe how the various components of the proposed research resource effort will be integrated, and how collaborations or subcontracts, if proposed, will be managed. Coordination of the awardee’s activities with those of other NIH supported public repositories must be described.

ii. Plans or processes for evaluating and continually maintaining safety regarding biohazards

iii. Plans or processes for evaluating and maintaining adherence to Health and Human Services and NIH guidelines and regulations.

iv. Procedures should be described for the evaluation of Resource and Service Section operations (e.g., by the External Advisory Board and Steering Committee) and for implementing recommendations resulting from such evaluations. The evaluation should include: 1) ability of the Section to promote its products, to meet product demand by the biomedical research community, (2) efficacy of product, service and information delivery both within and outside the Center; communication both within and outside the Center, and the ability to provide information about research advances and updates to the biomedical research community, and (3) feedback from users on catalog offerings, the ordering process and services. Mechanisms for regular solicitation of such feedback should be proposed.

v. Plans to communicate with Bioinformatics Section which will assist in maintaining the catalog of generated animal strains and biomaterials and communicating with customers.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Resource sharing Plans should only be included in the Overall component. Individual components will adhere to the overarching Resource Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Resource and Service Section)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

When preparing your application, use Component Type Project.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Disease Modeling Unit)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Disease Modeling Unit)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Disease Modeling Unit)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Disease Modeling Unit)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Disease Modeling Unit)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Disease Modeling Unit)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Disease Modeling Unit)

Specific Aims: Describe at least three demonstration disease modeling research projects aimed at full utilization of the advances of genomic medicine with the goal of creating precision animal models for early translation of basic research discoveries, and testing their feasibility and potential clinical benefits. Describe Disease Modeling Unit activities to generate precision animal models to evaluate unique human genomic variants nominated by the research community for cost effective high-throughput testing in an animal model pipeline.

Research Strategy: The Disease Modeling Unit will create precision animal models and test their predictive value in understanding fundamental disease pathology and pathogenesis as well as potential therapeutic target validation or clinical translation. Several demonstration projects should be developed at the beginning, while a major focus of the Disease Modeling Unit in follow-up years should be to fulfill the needs of the projects developed on the basis of community-wide nominations. It is expected that the Disease Modeling Unit will utilize the advances of in vivo genome editing technologies to accelerate the use not only of traditional animal model species, such as rodents, but also fish and large animal species, such as pigs and monkeys. Created animal models should precisely recapitulate specific alleles and genomic, proteomic, metabolomic and other biological indicators of human disease. To conduct these activities, the Disease Modeling Unit should include: an integrated surgical/pathology laboratory for diagnostic profiling, phenotyping and imaging; genomic and other omics laboratories; and facilities to perform drug testing and pharmacological/pharmacodynamics modeling. Wider-ranging projects that will go beyond analysis of single gene, gene variants or small number of variants are encouraged, for example, to explored mid- and high-throughput screening systems in appropriate animal species for testing a large number of pharmacogenomics variants with the eventual goal of target validation or guiding patient treatments. To perform such activities, the Center should have built-in infrastructure and relevant expertise. Applications advancing the use of faithful animal models for personalization of the patient treatment in co-clinical trials will be considered as well. Such models are expected to have direct impact on refining clinical trial capacity to stratify patients most appropriate for new target therapies and combinations of therapy that are in development.

Additional items to be addressed include:

i. Describe each demonstration project, including its testable hypothesis, scientific integration with the proposed organizing framework and a rationale for how each project will help, within the funded period, generate sufficient results to evaluate function and capacity of the Disease Modeling Unit.

ii. Provide details on techniques, methods and available expertise.

iii. Demonstrate utilization of new technologies for creating precision animal models such as targeting multiple genes/regions simultaneously; conducting semi and high throughput screenings; applying advances of regenerative biology and stem cell research; and allowing studies of gene and nucleotide variant function in the environment with the best approximation to humans (or even using animals carrying humanized or equivalent variants).

iv. Present plans for submitting the generated information to the Bioinformatics Section for evaluation and refinement of the models.

v. Statistical and analytical approaches should be described clearly and completely and placed in the research project section where the data are obtained.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Resource sharing Plans should only be included in the Overall component. Individual components will adhere to the overarching Resource Sharing Plan.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Disease Modeling Unit)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

The U54 application is a multi-Component application, with an "Overall" Component that is the aggregate of all sections and units of the Center: Coordination Section, Preclinical/Co-Clinical Section, Bioinformatics Section, Resource and Service section and Disease Modeling Unit. During the review process, "Merit Descriptors" (outstanding, acceptable, unacceptable) will first be provided in individual Reviewer's critiques for the Coordination Section, Preclinical/Co-Clinical Section, Bioinformatics Section, Resource and Service Section and Disease Modeling Unit. The three potential Merit Descriptors are outstanding, acceptable, or unacceptable. Then, numerical scoring of the application will be assigned for the Overall application. In the detailed sections below, each of the five Component's Review Criteria appear in the standard order used in FOAs.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the Center proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Center that by its nature is not innovative may be essential to advance a field.

Does the Center address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the Center are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition to the standardized criteria above, the following will be evaluated as part of the Significance score for the Overall Component. Does the Center have the potential to serve the needs of investigators in a variety of research areas and will it be available on a local, regional and national basis? Does the application address an important medical problem, and will it help to design and create advanced and predictive animal models? Was sufficient justification provided to support proposed project activities as a function of the Center?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the Center?

In addition to the standardized criteria above, the following will be evaluated as part of the Investigator(s) score for the Overall Component. Are PD(s)/PI(s), Section Head(s), and Project Lead(s) appropriately trained and suited to manage the Center? Will required bioinformatics and clinical expertise be present among Preclinical/Co-Clinical Section and Bioinformatics Section leadership? Is a plan for coordinating the activities and interactions of participating senior investigators present?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition to the standardized criteria above, the following will be evaluated as part of the Innovation score for the Overall Component. Do the design of the Center and overall objective of the program utilize innovative technologies and approaches, which will significantly accelerate application of advances in basic science for the medical benefits?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Have investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the Center involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Is the process by which the research community can nominate unique human genomic variants for a cost effective high-throughput testing in animal model pipeline described? Does the plan include measures to improve the animal model creation and validation pipeline and potential availability of additional funds from other NIH Institutes and funding agencies?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the Center proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Additional Review Criteria for Coordination Section

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate merit descriptor (outstanding, acceptable, unacceptable). An application does not need to be strong in all categories to be judged likely to have major scientific impact.

• Are there a clear and effective structure and a plan for coordination and management of the Center?
• Is the plan for outreach and recruitment of the community-based nominations of the human allele variants for the generation of precision animal models presented and adequate?
• Are the processes for the evaluation of progress across the Center and communication strategies to manage and track progress sound and robust?
• Is the utilization of the External Advisory Board for oversight and monitoring of different aspects of the center's function, including prioritization, and problem identification and resolution likely to be effective?
• Are plans for the following adequate: Coordination Section functions in regard to overall mission of the Center; monitoring of timelines for achieving milestones; appropriate prioritization of activities; provision of additional communication and data to the ORIP/DPCPSI/OD if needed?

Additional Review Criteria for Preclinical/Co-Clinical Section

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate merit descriptor (outstanding, acceptable, unacceptable). An application does not need to be strong in all categories to be judged likely to have major scientific impact.

• Are Preclinical/Co-Clinical Section's access to high quality patient clinical information (such as electronic medical records) and high quality genetic/omics data sufficient to formulate the medical problem requiring precision animal models?
• Will the Section be capable of collaborating with institutional clinical research or health-care delivery systems to facilitate enrollment and collect information from patient clinical-grade samples if required?
• Is strong supporting evidence provided for potential patient benefit from the use of precision animal models?
• Is there a clear plan for active participation in evaluation of the community-based nominations of the human allele variants for the generation of precision animal models and in analysis of the animal model discoveries for validation purposes as well as refinement of the models provided?
• If the project involves clinical research, are the plans for protection of human subjects from research risks, and inclusion of minorities and members of both sexes/genders, as well as the inclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Additional Review Criteria for Bioinformatics Section

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate merit descriptor (outstanding, acceptable, unacceptable). An application does not need to be strong in all categories to be judged likely to have major scientific impact.

• Have the Section Lead(s) and other key personnel demonstrated a record of directing informatics activities related to a Bioinformatics Section?
• Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center?
• Is the plan to develop methods to track experiments, document workflows and link this information to databases adequate?
• Are collaborations with other Sections and Units of the Center well described? Does the Bioinformatics Section assistance in active program for monitoring and collecting information on the impact of the Center’s ongoing activities on biomedical research innovative and adequate?
• Are Bioinformatics Section Lead(s) and other key personnel appropriately trained and assigned clear responsibilities in regard to handling a large amount of data from animal models, cross-referencing and analyzing this information in parallel to existing clinical data to enable comprehensive overview, developing hypotheses and driving research activities?
• Is a plan for maintaining the public website as well as highly organized, annotated and user-friendly databases to inform the public and private industry in the creation and use of predictive animal models presented?

Additional Review Criteria for Resource and Service Section

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate merit descriptor (outstanding, acceptable, unacceptable). An application does not need to be strong in all categories to be judged likely to have major scientific impact.

• Does the plan describing the design and development of the Resource and Service Section include future capacities of the research resource; procedures for acquisition, evaluation, cryopreservation, and distribution of animal model, germ lines and related biomaterials; and pathogen screening?
• Is the management plan for the research project adequate to support achievement of the proposed goals and milestones?
• Will the plan for collaboration with the Bioinformatics Section to design and develop a database and a free public homepage provide a user-friendly accounting of the resource’s holdings?
• Are the efforts that will be applied by the Section to enhance the capacity and evaluate the process of the Center to engage biomedical researchers and encourage requests for living and cryopreserved animal strains and related biomaterials well described?
• Are procedures for quality control, data collection, analysis, and diagnostic verification sufficient to maintain high quality standards of animal strains, related biomaterials and services provided to the biomedical research community? Will created resources optimize reproducibility of studies and assure scientific rigor and transparency?
• Are mechanisms in place for regular communication with biomedical researchers to encourage requests for living and cryopreserved animal strains and related biomaterials as well as for associated services?
• Is there evidence of an appropriate administrative structure to support and maintain the research resource plan of the Center, and to maintain communication with other NIH supported repositories?
• Are plans for handling requests for resources adequate? Are there plans for periodic assessments of performance, including timelines and milestones?

Additional Review Criteria for Disease Modeling Unit

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate merit descriptor (outstanding, acceptable, unacceptable). An application does not need to be strong in all categories to be judged likely to have major scientific impact.

• Are the conceptual framework, testable hypothesis, design, methods and analyses adequately developed, well integrated, well-reasoned and appropriate to demonstration disease modeling research projects aimed at utilization of advances in genomic medicine for creating precision animal models?
• Do demonstration disease modeling research projects utilize current advances of genome editing, stem cell biology and other cutting-edge technologies?
• Does the Disease Modeling Unit have adequate expertise and capacities to generate precision animal models for evaluating unique human genomic variants nominated by the research community?
• Is the choice of a particular animal species as a model system for the human disease well justified?
• Will the created animal models be able to recapitulate specific alleles and genomic, proteomic, metabolomic and other biological indicators of specific human disease?
• Are plans for interaction with other components of the Center, Coordination Section, Preclinical/Co-Clinical Section, Bioinformatics Section, and Resource and Service Section well described?

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed Center involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Not Applicable

Not Applicable

Not Applicable

As applicable for the Center proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by the Center of Scientific Review in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• Will be discussed and assigned an overall impact score.
• Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the NIH Council of Councils. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 75 and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Leading the project as a whole, and agree to accept close assistance, advice, coordination, and collaborate with the ORIP/DPCPSI Project Scientist and other Center awardees.
• Planning, direction, and execution of the proposed project will be solely that of the PD(s)/PI(s). They will determine experimental approaches, design protocols, set project milestones and conduct experiments.
• Participating in group activities, including the Steering Committee, to share design and analysis techniques and promote comparability across studies wherever possible.
• Ensuring active participation of partner sites and collaborators in group activities, if applicable.
• Implementing Steering Committee recommendations for designing, implementing, evaluating, and disseminating demonstration disease modeling research projects, as appropriate and feasible.
• Adhering to the general NIH policies regarding sharing resources, data release, and resource sharing, as well as the specific data and resource-sharing policies proposed in the application, as modified by any negotiation prior to award.
• Submitting periodic progress reports in a standard format, as agreed upon by the Steering Committee.
• Attending and participating in Steering Committee meetings and accepting and implementing the guidelines and procedures, as appropriate.

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist is an ORIP/DPCPSI/OD/NIH staff member who will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the program and that NIH staff will be given the opportunity to offer input to this process. The Project Scientist will participate as a member of the Steering Committee and will have one vote. The Project Scientist will have the following substantial involvement:

• Participating with the other Steering Committee members in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Project Scientist will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities among and for the Center awardees, including acting as a liaison to the NIH, and as an information resource for the Center awardees about other research activities. The Project Scientist will also coordinate the efforts of the program with other groups conducting similar studies.
• Attending all Steering Committee meetings as a voting member and assisting in developing operating guidelines, quality control procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist will be responsible for working with the Coordinating Section as needed to manage the logistical aspects of the program.
• Reporting periodically on the progress of the program to the ORIP and DCM Directors.
• Retaining the option to recommend the withholding or reduction of support from any project that fails to achieve its goals or comply with the Terms and Conditions of award.
• Serving as a liaison between the Steering Committee and the External Advisory Board, attending External Advisory Board meetings in a non-voting liaison member role, and arranging for timely preparation and distribution of meeting minutes.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the program.

Other ORIP/DPCPSI/OD/NIH staff may assist the awardees as designated by the Program Official.

Additionally, an ORIP/DPCPSI/OD/NIH Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The Program Official may withhold or reduce support from any awardee that fails to achieve its goals or comply with the Terms and Conditions of Award. The assigned program official may also serve as an NIH Project Scientist.

The Steering Committee will:

• Participate in monitoring "day to day" scientific progress of the research project plan, assessing recruitment and progress of the milestones.
• Convene monthly video or audio teleconferences and yearly in person meetings to monitor progress on the research project plan and to address issues or activities that impact the project, identify areas of shared interest and potential for collaboration.
• Establish workgroups for specific tasks as the Steering Committee deems appropriate.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to develop appropriate strategies and tools to develop precision animal models. The Center awardees, Project Scientist, and Steering Committee will meet at least one time per year in person and monthly on conference calls as needed to share information on data resources, methodologies, analytical tools, as well as data and preliminary results. Key co-investigators and pre- and postdoctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, in addition to the PIs, are eligible to attend these meetings.

The Steering Committee will be responsible for coordinating the activities being conducted by the program. The Steering Committee membership will include one ORIP/DPCPSI Project Scientist and the PD/PI from each Center Section and Unit. The Steering Committee may add additional members, and other government staff may attend the Steering Committee meetings as desired.

To address particular issues, the Steering Committee may establish working groups as needed, which will include representatives from the program and the NIH and possibly other experts.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Oleg Mirochnitchenko, Ph.D.
Office of Research Infrastructure Programs (ORIP)
Telephone: 301-425-0479
Email: oleg.mirochnitchenko@nih.gov

Mark Caprara, Ph.D.
Center for Scientific Review
Telephone: 301-613-5228
Email: mark.caprara@nih.gov

Donna James
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-827-8063
Email: james@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.