NIH’s new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

Required Application Instructions

It is critical that applicants follow the 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) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 demonstration pipelines for pre-clinical scientific discovery, disease modeling and development of interventions based on innovative animal models, which 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 and creation of interspecies somatic hybrids to enhance the predictive value of pre-clinical studies based on the use of precision animal models. 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 work on several focused projects. However, it is expected that a specific Center will maintain multifaceted research activities to build core model systems that can be adjusted as required to accommodate a broad spectrum of diseases. Each center should have a set of required units, including pre-clinical or co-clinical sections, 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 value of newly created disease models in pre-clinical 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, which require 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, and 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 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. 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 /NIH-OD convened an NIH symposium, October 28 29, 2013, 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 the symposium and the recommendations of the biomedical community provide the basis for this FOA.

Research Objectives

Projects supported by ORIP under this FOA are intended to provide support for demonstration 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 trials.

Precision animal models can be used to investigate the mechanism of disease, for target identification and validation, development of diagnostics, biomarkers and new drugs, and for testing and optimizing 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 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 and Disease Modeling Unit with at least three independent projects per Center. The proposed cooperative agreements will develop the coordination center and modules, which will be integrated in a functional pipeline. This pipeline will help to overcome major bottlenecks between diagnosis of human disease, understanding its mechanism 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. Of specific interest are studies aimed at understanding the functional significance of different coding variants.
• Creating animal model systems that have the potential to be used in pre-clinical 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.
• Creating new and improved disease taxonomy and phenotype ontologies to better assist translation of specific patient information to the most appropriate animal model system and disease category. 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 the existing human/animal comparative pathology and imaging centers. This will require developing pathology technologies and resources to support disease phenotyping efforts as well as pre-clinical 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. 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.

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 units:

• 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 section(s) consistent with achieving the goals of the program.
• The Preclinical/Co-clinical Section will be responsible for clinical interactions: 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 application to 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 pre-clinical 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) is 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 the animal models for specific pre-clinical applications.
• The Bioinformatics Section will conduct computational research activities to support decision-making processes regarding choosing the specific genetic alleles or variations to model in a particular animal species, and predicting possible outcomes of the genetic/cell interventions and predicting expected phenotypic features. An important function of this section will be collecting data from the animal model generation process, genotyping and phenotyping.
• The Disease Modeling Unit will develop at least three projects that create and test precision animal models. This unit should have sufficient expertise to use 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.

Steering Committee: Each Pilot Center should have a Steering Committee. It 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.

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 the progress and scientific opportunities, and evaluate the progress and the effectiveness of interaction among participants.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to 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) (formerly CCR) 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

Due to the complex nature of the projects and the focus on collaboration and expertise sharing, this FOA requires participation of teams with expertise in basic sciences, genomics/bioinformatics, animal biology and clinical research. The Center Program Director/Principal Investigator (PD/PI) or contact PD/PI for applications with multiple PDs/PIs must be a scientist with animal disease modeling experience. PD/PIs and co-investigators may come from different institutions.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants can access the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

Most applicants will use NIH’s ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	12
Admin Core (Use for Coordination Section)	6
Core (Use for Preclinical/Co-Clinical Section and Bioinformatics 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
• Coordination Section: required
• Preclinical/Co-Clinical Section: required
• Bioinformatics Section: required
• Disease Modeling Unit: at least one is required

When preparing your application in ASSIST, use Component Type Overall .

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

SF424 (R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

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

Center organization: A diagram should 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.

Project/Performance Site Location(s) (Overall)

Enter primary site only. However, if one of the PD/PIs for the center is named from a different institution, include information for that site as well.

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.

Research & Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) or all PDs/PIs, if it is multiple PI application.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.

Budget (Overall)

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.

PHS 398 Research Plan (Overall)

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

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

ii. 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 an additional senior/key personel with primary expertise in bioinformatics and clinical research. Applications should demonstrate plans for ongoing communication and sharing of data and resources within the Center.

iii. Disease Modeling Projects. Briefly describe each project, including its scientific integration with the proposed organizing framework and a rationale for how each project will, within the funded period, generate sufficient results 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 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 Unit should be uploaded as a single attachment.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, use Component Type Admin Core.

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

SF424 (R&R) Cover (Coordination 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 (Coordination Section)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Coordination 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) (Coordination 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 (Cordination Section)

• 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 (Coordination 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 (Coordination Section)

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 research center by PDs/PIs, who will have expertise in a particular area of research activities. This unit will effectively coordinate interactions and collaboration of the 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 project, and how it will support achievement of the proposed goals and milestones. 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.

Describe External Advisory Board. 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.

The Coordination Section should coordinate participation in Center program evaluation activities, including progress reports, site visits, and providing 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 (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Coordination Section)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Coordination Section)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, 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 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 (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 unit interaction 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 be the key in generating testable hypothesis and linking clinical information to potential comprehensive functional annotation gained in animal models. That should be done under the patient protection policies within the institution’s relevant regulations and guidelines. The Preclinical/Co-Clinical Section should have a 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.

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 the 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, studying pharmacodynamic/pharmokinetic 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 refining 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.

Protection of Human Subjects: If Core services involve human subjects, (e.g., recruitment, screening, evaluation, biobanking), discuss the Human Subjects protections following the SF424 Guide instructions. If all of the individual projects accessing the Core have their own Human Subjects sections, this should be clearly stated in this section.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Preclinical/Co-Clinical Section)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Preclinical/Co-Clinical Section)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, 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 (Bionformatics 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 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 (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. This unit will also be responsible for development of methods to track experiments, document workflows and link this information to databases. During research investigations, large numbers 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 an hypothesis to drive research activities. It also should enable creation of the human/animal database exchange that will drive the dissemination of both electronic (data) and physical (animal models) information and to 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 the goals of the program. 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 Integrated Bioinformatics Unit 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 the 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 Disease Modeling Projects 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.

Protection of Human Subjects: If Core services involve human subjects, (e.g., recruitment, screening, evaluation, biobanking), discuss the Human Subjects protections following the SF424 Guide instructions. If all of the individual projects accessing the Core have their own Human Subjects sections, this should be clearly stated in this section.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Bioinformatics Section)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Bioinformatics Section)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

When preparing your application in ASSIST, 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 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.
• The Director and research team of this unit should have appropriate experience and training to conduct of studies most relevant for a particular disease and animal species.
• Each project of the Disease Modeling Unit must include clinical researcher/s (as co-investigators) with primary expertise in an area of pilot project/s focus. Additional key personnel should provide the appropriate breadth and balance of basic sciences and clinical research expertise.

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 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.

Research Strategy: The Disease Modeling Unit will create precision animal models and test their predictive value in understanding fundamental disease pathology and pathogenesis, potential therapeutic target validation or clinical translation. 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 capacity to perform drug testing, and pharmacological/pharmacodynamics modeling. Wider-ranging projects that will go beyond analysis of the single gene or gene variants or their small numbers are encouraged, for example exploring mid- and high-throughput screening systems in appropriate animal species to test a large number of the 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 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.

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, 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.

Protection of Human Subjects: If Core services involve human subjects, (e.g., recruitment, screening, evaluation, biobanking), discuss the Human Subjects protections following the SF424 Guide instructions. If all of the individual projects accessing the Core have their own Human Subjects sections, this should be clearly stated in this section.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) 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: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report (Disease Modeling Unit)

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

PHS 398 Cumulative Inclusion Enrollment Report (Disease Modeling Unit)

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. 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.

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.

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 Applying Electronically.

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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research 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 units of the Center: Coordination Section, Pre-clinical/Co-clinical Section, Bioinformatics and Disease Modeling Section. During the review process, "Merit Descriptors" will first be provided in individual Reviewer's critiques for the Coordination Section, Pre-clinical/Co-clinical Section, Bioinformatics 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 project 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 project 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 project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project 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 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 regarding proposed projects that will be conducted more efficiently as a center?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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 project? 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?

Innovation

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 the advances in basic science for the medical benefits?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the O? 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?

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 children, justified in terms of the scientific goals and research strategy proposed?

Environment

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?

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.

• Are there a clear and effective structure and plan for coordination and management of the Center?
• Are the process of the evaluation of progress across the Center and communication strategies to manage and track progress sound and robust?
• What is the likely effectiveness of the utilization of an external advisory board for oversight and monitoring of different aspects of the center's function, including prioritization, and problem identification and resolution?
• Are plans for the following adequate: Coordination Section functions in regard to overall mission of the Center; monitoring timelines for achieving milestones; ensuring appropriate prioritization of activities; providing additional communication and materials to the ORIP/DPCPSI/OD if needed?

Scored 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 score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact.Are Preclinical/Co-Clinical Sections 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 to collaborate 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 a clear plan for active participation in analysis of the animal model discoveries for validation purposes as well as refinement of the model provided?
• If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Scored Review Criteria for Bioinformatics Section

• 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.Have the PD/PI(s) and other key personnel demonstrated a record of directing informatics activities related to an 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 Bioinformatics Section PD/PI(s) and other key personnel appropriately trained and assigned clear responsibilities in regard to handling a large number of data from animal models, to cross-reference and analyze this information in parallel to existing clinical data to enable comprehensive overview, developing hypothesis and drive research activities?

• 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.Are the conceptual framework, testable hypothesis, design, methods and analyses adequately developed, well integrated, well-reasoned and appropriate to disease modeling research projects aimed at utilization of the advances of genomic medicine with achievements of creating precision animal models?
• Do Disease Modeling projects utilize the current advances of genome editing, stem cell biology and other cutting-edge technologies?
• Is the choice of the particular animal species as a model system for the human disease well justified?
• How well 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, Pre-clinical/Co-Clinical Section, Bioinformatics Section well described?

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.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six 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.

Inclusion of Women, Minorities, and Children

When the proposed project 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 children 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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project 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.

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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 for 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 submitted in response to this FOA. 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.

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.

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.

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 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 awardees.
• Planning, direction, and execution of the proposed project will be solely that of the Principal Investigators. They will determine experimental approaches, design protocols, set project milestones and conduct experiments.
• Participating in group activities, including 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 Disease Modeling 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 a scientist of the ORIP/DPCPSI staff 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 awardees, including acting as a liaison to the NIH, and as an information resource for the 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 logistic aspects of the program.
• Reporting periodically on the progress of the program to the ORIP and DCM Director.
• 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.
• Assisting awardees in the development, if needed, of policies for dealing with situations that require coordinated action.
• 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 staff may assist the awardees as designated by the Program Official.

Additionally, a NIH ORIP/DPCPSI 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 director 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 video or audio teleconferences and yearly 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 awardees and the Project Scientist will meet as the program Steering Committee 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 component. 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 Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Oleg Mirochnitchenko, Ph.D.
Office of Research Infrastructure Programs (ORIP)
Telephone: 301-435-0749
Email: [email protected]

Ross D. Shonat, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-2786
Email: [email protected]

Jenelle D. Wiggins
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0843
Email: [email protected]

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 Parts 74 and 92. ICs should insert IC-specific regulations if applicable.