Part 1. Overview Information

Key Dates

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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is two-fold: 1) to encourage submission of applications to do more in-depth phenotyping on investigator-selected cohorts of embryonic lethal or subviable Knockout (KO) mouse strains generated by the International Mouse Phenotyping Consortium (IMPC) of which the NIH Knockout Mouse Program (KOMP2) is a member; and, 2) to encourage submission of applications to use investigator-selected embryonic lethal, perinatal lethal, or subviable IMPC-generated KO mouse strains in hypothesis-driven research focused on placental defects, structural birth defects, and/or fertility issues. The KOMP2 Program is in its second phase (2017-2021) of production and primary phenotyping of KO strains, and it is anticipated that the number of available strains for analyses by the research community will increase exponentially.

In-depth phenotyping and further research using embryonic lethal, perinatal lethal, and subviable KO mouse strains are of strategic importance for several reasons. Most obviously, these genes are critical to embryonic growth, differentiation, and organogenesis. Early lethals have defects in pre- and peri-implantation processes in embryonic or extra-embryonic tissues. Mid-gestational lethals have defects in organogenesis. Lethality in the fetal or immediate perinatal periods (late lethals) indicates failures in the transition to adult functioning organ systems. These mouse strains are extremely useful as models for a range of congenital human diseases, structural birth defects, infertility, and spontaneous miscarriage. Viable heterozygote alleles are likely to be widely represented in human disease because of their haploinsufficiency or dominant phenotypic effects. So, there is significant and complementary value in also phenotyping heterozygote mutants of these KO strains for clinical phenotypes.

Background

The mouse has long been an important mammalian model system for the study of gene function in human health and disease. Mouse mutants with phenotypes that mimic human traits have served as critical research tools in understanding the genetics underlying mammalian biology. Equally important, mouse mutants have been the tools used to begin to understand gene function and pathways as the science has moved from gene identification to mammalian functional genomics.

In 2006, the Trans-NIH Knockout Mouse Project (KOMP) was launched with the goal of generating KO mutations in 8,500 genes in C57BL/6 mouse lines by deleting all or most of the exons in target genes or producing knockout-first conditional ready alleles. Together with the European Conditional Mouse Mutagenesis Program (EUCOMM) and the North American Conditional Mouse Mutagenesis Program (NorCOMM), these efforts produced knock out embryonic stem cells for 18,000 protein coding genes, as well as live mouse lines, frozen embryos and sperm, and vectors which are available from public repositories under the auspices of the International Knockout Mouse Consortium (IKMC). Thus, the first phase of this resource was completed in 2011, and attention turned toward implementation of the next phase (KOMP2) for high throughput production and phenotyping of KO mouse strains.

The goal of the KOMP2 program, started in 2011, is to generate and systematically phenotype lines of mice that carry knockouts for a genome-wide collection of mouse genes in order to define the in vivo function of mammalian genes, provide access to and information on unannotated genes, and identify new models of human disease. Along with international partners under the auspices of the IMPC, a coordinated phenotyping effort is underway employing common and standardized phenotyping platforms for adult mice with common quality control standards eliminating the redundancy and waste inherent in the "cottage industry" approach (www.mousephenotype.org). Through this effort, the First Phase of the KOMP2 Program (2011-2016) has succeeded in phenotyping 2500 mutant mouse lines. The Second Phase of KOMP2 (2017-2021) aims to build upon the success of phase 1 and add 3,000 more knockouts. To achieve this, three Production/Phenotyping Centers and one Data Coordination Center is currently funded by the NIH. These Centers are primarily using CRISPR/Cas9 knockout technology to accelerate the rate of production of mutant alleles. The resulting global resource of KO mice and associated database of gene function is building a foundation that will revolutionize both basic and clinical research for the next 20-25 years.

Through the IMPC-KOMP2 effort, ~9,051 KO mouse lines have been generated and are being phenotyped. Indeed, during examination of the first ~5,327 mutant lines produced, 1,274 displayed embryonic lethality with an additional ~509 strains identified as being "subviable" (http://www.mousephenotype.org/data/embryo; data posted as of June 26, 2019). These data are consistent with earlier analyses and confirm that approximately 30% of mammalian genes are essential for normal embryonic growth and development. Based on an analysis of data in the Jackson Laboratory Mouse Genome Informatics (MGI) database, of the 60% of embryonic lethal strains that exhibit abnormal anatomy, 30% will have urogenital, palate, thymus, lung, trachea, gut, liver, diaphragm, spleen and pancreas defects; 28% will have brain, spinal cord, eye, or ear defects; 26% will have cardiac defects; and, 15% will have skeletal and limb defects. As KO strains continue to progress through the pipeline and new embryonic lethal and subviable strains are phenotyped, primary tier phenotype information is being made available to the community via the IMPC portal (www.mousephenotype.org; see "Embryonic Phenotyping" for updated data). After the completion of the first phenotyping phase (2011-2016), a comprehensive analysis of the embryonic lethal pipeline was undertaken by the IMPC and published (https://commonfund.nih.gov/KOMP2/programhighlights#embryonic). During the Second Phase (2017-2021) of KO mouse production, hundreds of new embryonic lethal and subviable KO strains are being generated and documented in the IMPC database as an invaluable resource for the research community.

Scope

A tiered triage approach to the phenotyping of embryonic lethal KO strains to facilitate flexibility in experimental design and economize on breeding strategies is in place. Primary tier screening begins with a careful evaluation of genotype ratios during breeding to generate adult cohorts for the adult phenotyping pipeline. A mid-gestation stage of E12.5 is the initial reference time point for a "first look" at strains deemed embryonic lethal or subviable and for assessment of developmental anomalies. Based on the E12.5 analysis, embryos are triaged for further analyses at either earlier or later time points (e.g., E9.5 or E14.5 in KOMP2 or E18.5 across other IMPC centers) as recommended by the Bloomsbury Report. The established phenotyping pipeline includes collection of robust, three-dimensional imaging datasets that are accessible and free to be mined through the IMPC data portal (http://www.mousephenotype.org/data/embryo). In addition to the embryonic lethal KO strains, it is important to note two other cohorts of interest: the estimated 15% of perinatal lethal KO strains and 10% of subviable KO strains. These represent cohorts for further study as these are likely to represent models of human structural birth defects as well.

Depending upon the data available from the embryonic lethal pipeline primary tier screening being performed by the IMPC centers, investigators may consider three options when applying for funding through this FOA:

• Pursue non-hypothesis-driven, non-mechanistic secondary- and/or tertiary tier screening on a select cohort of IMPC-generated KO strains using various approaches. 1) Studies could focus upon the acquisition of more detailed morphological information with any of a variety of 3D imaging modalities (e.g., magnetic resonance, CT, high resolution epifluorescence microscopy, OPT, and optical coherence tomography). It is impossible to dictate the "best" stage or modality for imaging to discover novel phenotypes as developmental processes vary by embryonic stage and the interests of the investigators should dictate these aspects. The IMPC will continue to play a leadership role in standardizing operating procedures for 3D imaging of embryos in the same manner that they have developed the common protocols for adult phenotyping. Potential applicants are encouraged to visit the IMPC website for updated information [http://www.mousephenotype.org/data/embryo]. 2) An optional approach for characterization of gene function would be to perform mRNA expression profiling using RNA sequencing (RNAseq) of embryonic tissues to measure global perturbations caused by the KO. Sequencing technologies are continuously evolving; therefore, it is conceivable that this could be applied to embryonic mouse screening, too. 3)Tertiary tier screening would involve more focused phenotyping of strains of interest to individual investigators. These types of analyses could include, but are not limited to, more detailed immunohistochemistry, laser capture micro-dissection, or the development of cell-based assays.

  • It is anticipated that secondary and tertiary level phenotyping will involve collaborations between the IMPC production centers and investigators interested in advancing their research agendas by pursuing analyses of focused sets of mutants. An important aspect of secondary and tertiary tier screening will be the integration of phenotypic data into the existing database supported by the IMPC. Phenotypic data generated through this initiative are required to be deposited in the IMPC database as noted in Section IV.2. Resource Sharing Plan. The applicant must contact the IMPC data coordinating center at the European Bioinformatics Institute (the EBI-KOMP2 Mouse Phenotyping Informatics Infrastructure Consortium; Ann-Marie Mallon at a.mallon@har.mrc.ac.uk) to develop a data sharing strategy and to request a supporting letter of agreement for deposition of phenotypic data to IMPC. Please use "NIH PAR-20-137" as the subject line of your email. The letter of support should specify the negotiated cost of data deposition and the cost should be included in the requested budget.

• Pursue a combination of non-hypothesis-driven, non-mechanistic secondary tier screening on a select cohort of IMPC-generated KO strains and hypothesis-driven aim(s) on selected strains. As the KOMP2 phenotyping effort continues (current phase, 2017-2021) it is clear that there will be a significant increase in phenotypic data available on embryonic lethal, perinatal lethal, and subviable KO strains. In an effort to encourage the further use of these data and strains, applications that make use of these IMPC-generated strains, further the phenotyping effort, and incorporate hypothesis-driven research aim(s) willedw be considered under this FOA. For these studies applicants can use a combination of IMPC and other resources to address their hypothesis.

• Pursue strictly hypothesis-driven research on a select cohort of KOMP-IMPC-generated embryonic lethal, perinatal lethal, and/or subviable KO strains. Applications that have hypothesis-driven aim(s) to study the underlying mechanisms resulting in embryonic lethality, and/or perinatal lethality and/or subviability will also be considered under this FOA. For these studies applicants can use a combination of IMPC and other resources to address their hypothesis.

Research Interests of Participating Institutes

The participating NIH Institutes have provided a brief outline of their interests as they relate to the goals of this FOA. These mission statements are intended to indicate the breadth of the biomedical areas of interest.

NICHD

The NICHD is interested in the evaluation and use of embryonic lethal, perinatal lethal, and subviable KO strains exhibiting structural defects in embryonic development. This includes, but is not restricted to, defects affecting post-implantation development, gastrulation and organogenesis, especially those that affect multiple organ systems; limb, neural, cardio-vascular, musculoskeletal, urogenital, digestive, respiratory and lymphatic. Additionally, understanding potential links between fertility status and any co-morbid conditions in the subviable KO strains would be of interest. Finally, evaluation and use of KO lines with defects in trophoblast development, allantois-chorion fusion, or other aspects of placental development or function are of interest. The focus should be on the determination of placental etiology resulting in embryonic lethality at the pathohistological and molecular levels as well as delineating the possible regulatory mechanism(s) affected by loss of gene function.

NIDCR

The NIDCR supports research into all areas of dental, oral, and craniofacial biology including but not limited to: aspects of craniofacial development such as neural crest migrations and the regulation and disorders thereof; mineralized tissues; and, salivary gland development and function. Studies characterizing embryonic, perinatal, and adult phenotypes of KO mice relevant to dental, oral, and craniofacial biology are welcome.

ORWH

The Office of Research on Women’s Health (ORWH) is interested in co-funding applications that include adequate plans to address sex as a biological variable (SABV) including plans to disaggregate data by sex. There is a crucial need to address sex influences in basic, translational, interdisciplinary, behavioral, clinical, and/or health services research relevant to women's health, and, where appropriate, include both sexes to better understand the influence of SABV on health and disease (see linked document). Integrating the purposeful accounting for SABV in biomedical research from the most basic to the clinical and applied efforts, will fill gaps in our knowledge, will inform more effective, personalized approaches for women and men. For additional guidance, please look at the 2019-2023 Trans-NIH Strategic Plan for the Health of Women (https://orwh.od.nih.gov/about/trans-nih-strategic-plan-womens-health-research).

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

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

• 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are 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.

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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Mahua Mukhopadhyay, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6886
Email: mukhopam@mail.nih.gov

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

Research Strategy:

Applicants must clearly justify the approach they choose (non-hypothesis driven secondary screening, hypothesis-driven research, or a combination of the two) and how the chosen approach will utilize the KOMP2/IMPC resources.

Letters of Support: Applications must include a letter of support indicatingagreement from IMPC for deposition of phenotypic data. Funds should be included in the requested budget to cover the cost.

The following modifications also apply:

NICHD Plans for Sharing Human and Non-Human Data and/or Biospecimens

NICHD expects that data, biospecimens, and results of NICHD-funded research will be shared with the wider scientific community to the extent feasible and in a timely manner. NIH Data Sharing Policy expects the timely release and sharing of data to be no later than the acceptance for publication of the main findings from the final dataset. All NICHD applications, regardless of the amount of direct costs requested for any one year, are expected to include a Sharing Plan that addresses sharing of data as well as biospecimens, if applicable. Ideally, this plan would include submitting data or biospecimens to an appropriate repository. These plans will also be considered by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program.

Specifically, for human data, the NICHD encourages the use of the Data and Specimen Hub (DASH), a centralized resource for researchers to store and access de-identified data from studies funded by NICHD. They can also submit information about the location and availability of biospecimens to DASH, if applicable. Submission of data to the NICHD DASH is one way that grantees may meet the requirements of the NIH Data Sharing Policy and make study data available for secondary analyses. Information about DASH may be obtained at https://dash.nichd.nih.gov/

If use of DASH is not feasible, NICHD expects awardees to share data and/or biospecimens through other equivalent broad-sharing data and/or biospecimen repositories. For projects generating large-scale human genetic data, applicants should provide a Provisional or Institutional Certification specifying whether the individual-level data can be shared through an NIH approved repository, such as dbGaP, in line with the NIH Genomic Data Sharing Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html).

• It is required that the phenotypic data generated be made available to the research community through the existing database supported by the IMPC, of which the NIH KOMP2 is a member, at the European Bioinformatics Institute (EBI). The applicant must contact the IMPC data coordinating center at a.mallon@har.mrc.ac.uk (Attn: Ann-Marie Mallon) to develop a data sharing strategy and to request a supporting letter of agreement for deposition of phenotypic data to IMPC. Please use "NIH PAR-20-137" as the subject line of your email. The letter of support should specify the negotiated cost for data deposition. Funds should be included in the requested budget to cover the cost.

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 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.

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.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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). 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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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

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) 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. See Section III of this FOA for information on registration requirements.

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. 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.

Section V. Application Review Information

1. Criteria

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.

Significance

Does the project 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 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?

Will the data generated be of high value to the broad research community and enhance the KOMP2/IMPC resource?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? 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 project?

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?

Approach

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

Applicants must clearly justify the approach they choose: non-hypothesis driven secondary/tertiary screening, hypothesis-driven research, or a combination of the two. Does the application conducting non-hypothesis driven secondary or tertiary screening, and/or hypothesis-driven research utilize the KOMP2/IMPC resource? Will the approach chosen effectively utilize the KOMP2/IMPC resource by building upon the primary phenotyping of the IMPC mouse strains available to the community?

If the project 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?

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?

Protections for Human Subjects

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 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.

Vertebrate Animals

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.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by Center for Scientific Review (CSR), 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.

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

• 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.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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.

2. Administrative and National Policy Requirements

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.

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.

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.htmlhttps://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.htmlor 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.

3. Reporting

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 agreementsare 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.

Section VII. Agency Contacts

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: 301-637-3015

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

Mahua Mukhopadhyay, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6886
Email: mukhopam@mail.nih.gov

Kathryn Stein, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4653
Email: kathryn.stein@nih.gov

Rajeev Agarwal, Ph.D.
National Cancer Institute (NCI)
Telephone: (301) 496-8528
E-mail: agarwalraj@mail.nih.gov

Maqsood Wani, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-2270
Email: mw486e@nih.gov

Bryan S. Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email:rutbergd@mail.nih.gov

Section VIII. Other Information