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

Type 1 diabetes (T1D) is a complex autoimmune disease characterized by destruction of insulin-producing pancreatic beta cells, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. It is the most common form of diabetes in children and young adults, and accounts for approximately 80% of pediatric diabetes cases in the United States. The incidence of T1D is on the rise in the United States and worldwide. T1D is a complex disease with risk determined by genetic variants of varying effect sizes, unknown environmental triggers, and their interaction. The overall risk of T1D in the general population is 0.4%, but it is higher in relatives of patients for e.g. the average lifetime risk in siblings of patients is on average a 6% to 7%. Twin and family studies suggest that 40-50% of T1D susceptibility is due to genetic/familial factors. Early studies have shown that the HLA region on chromosome 6p21.3 is by far the strongest genetic determinant for T1D and accounts for approximately 40%-50% of the familial aggregation of T1D. The strongest association is with HLA DR and DQ, although additional genetic factors in the region may contribute to T1D risk.

Until 15-20 years ago, few non-HLA candidate genes had been identified. Increased sample sizes and development of high throughput genotyping, imputation and other robust technologies have led to the identification of over 50 loci contributing to T1D risk, see https://beta.immunobase.org/disease/T1D/. All these genetic loci that contribute to T1D susceptibility, explain about 80%-90% of its hereditability in European populations. The non-HLA loci identified have smaller effects on disease risk relative to HLA but comparable effect sizes to risk loci identified in other common human disorders. The insulin gene on chromosome 11p15 represents the second most strongly associated locus with T1D risk. The protein tyrosine phosphatase, non-receptor type 22 (PTPN22) (rs2476601 SNP), on chromosome 1p13, which encodes lymphoid specific phosphatase (LYP), a suppressor of T cell activation is associated with T1D. Other genes that modify T1D risk include the cytotoxic T-lymphocyte associated protein (CTLA-4), which is a negative regulator of cytotoxic T cells, the interleukin-2 receptor subunit alpha (IL2RA, CD25); protein tyrosine phosphatase, non-receptor type 2 (PTPN2); interferon-induced helicase (IFIH1); the basic leucine zipper transcription factor 2 (BACH2); and ubiquitin-associated and SH3 domain-containing protein A (UBASH3A). Most of the genes associated with T1D are in the immune pathway but evidence is accumulating that several genes are expressed in beta-cells and may affect beta-cell survival and function, especially in relation to inflammation, environmental stimuli and innate immune responses. For example, Gli-similar 3 protein (GLIS3) gene region has been linked to neonatal diabetes, T1D and type 2 diabetes. This protein has been implicated in the generation of beta cells, INS expression and beta-cell apoptosis.

Studies to understand the function of the variants associated with T1D risk have started shedding light on the mechanism of the loci associated with T1D risk. The association between HLA molecules and T1D is thought to result from genetic polymorphisms that encode for different amino acid residues in the peptide-binding pockets of HLA molecules which impact the binding affinity and repertoire of peptides that can be presented to T-cells. However, the molecular understanding of how HLA contributes to T1D still remains unclear due the large number of distinctive HLA alleles and unusual frequencies that make the overall mechanism difficult to interpret. The insulin gene, harbors 3 major insulin variable number tandem repeats (VNTR) according to the number of repeats. The highest risk is conferred by homozygosity for class I (shortest repeats). The insulin polymorphisms regulate the amount of insulin mRNA in the thymus and are likely to influence the development of immune tolerance to insulin. For PTPN22, a gain of function LYP variant is associated with suppression of TCR signaling and reportedly promotes the survival of autoreactive T-lymphocytes in the thymus. The PTPN22 locus has also been associated with effects on the function of effector T-lymphocytes, regulatory T-lymphocytes and B-lymphocytes in the periphery. For CTLA-4 an altered post-transcriptional regulation could mediate the association between CTLA-4 polymorphisms and T1D. It has been recently shown that Abatacept (CTLA4-Ig), which selectively binds to CD80/86, blocks the interaction with CD28 and modulates co-stimulation transiently halts beta-cell loss in individuals recently diagnosed with T1D. IL2RA variants causing abnormalities in sensitivity to IL2, which is critical to T-regulatory cell function, may alter the balance between T-regulatory cells and T-effector cells and thus increase risk of T1D. PTPN2 may induce beta-cell apoptosis after interaction with increased local levels of interferon. IFIH1 encodes melanoma differentiation-associated protein 5 (MDA5), which binds to double stranded RNA viruses and thus mediates the innate immune system’s interferon response to certain viruses. BACH2 regulates proinflammatory cytokine-induced apoptotic pathways in pancreatic beta-cells by crosstalk with PTPN2. UBASH3A down regulates the NF-kB signaling pathway upon T-cell receptor stimulation, thus reducing IL2 gene expression.

Although work is ongoing to study the mechanism of the genes, this RFA would encourage the expansion of this promising beginning, allow additional genes/loci to be evaluated for their function, and shed light on the pathophysiology of the disease toward new drugs and better-tailored therapies. There is evidence that most of the T1D-associated SNPs are in regulatory (noncoding) regions of the genome, rather than protein-coding regions, of the genome. These are likely involved in gene regulation in specific cell types. Mechanistic dissection of such signals remains challenging, in part because it has been far harder to attribute the functional impact of such variants, and in part because it has proven difficult to robustly connect non-coding risk variants to their downstream effectors (be those protein-coding genes, or other entities such as lncRNAs). However, dropping sequencing costs and new technologies for high-throughput assessment of variant function (e.g., massively parallel reporter assays) and cis-relationships (e.g., cis-eQTLs, Hi-C, ChIA-PET) have opened new possibilities for the systematic investigation of the regulatory genome. The application of these and other approaches has provided a steady increase in the numbers of GWAS loci at which it has been possible to isolate the specific causal (non-coding) variants and demonstrate their impact on the regulation of expression of nearby genes. The disease-associated regulatory sequences so implicated may represent enhancer regions that connect to multiple promoters or chromatin domains that play a role in local genome architecture and looping dynamics; alternatively, they may code for one of the varieties of non-coding RNAs involved in transcriptional regulation or nuclear organization. In parallel with these advances in providing tools to highlight likely causal variants and effectors, the introduction of CRISPR/Cas9 genome editing is providing new opportunities for the direct functional interrogation of non-coding variants of interest and the effector genes through which they are presumed to operate. The new technologies being developed will help us connect the many millions of non-coding variants revealed by whole genome sequencing to disease risk and increase our understanding of the biological pathways underlying disease and the specific biological targets that can alter disease. These biological insights in turn can be translated to clinical benefits, including reliable biomarkers and effective strategies for screening and disease prevention, more rational drug design, and better tailored therapies.

Thus, NIDDK is soliciting applications to this RFA to address the overarching goals of 1) accelerating the pace of understanding of the genetic architecture of T1D, 2) identifying effector transcripts with predicted causal relationship to T1D, 3) validating the strength of predicted effector transcripts through experimental work and their placement in networks, and 4) making this information broadly available to the scientific community to foster fundamental and clinical research through the T1D portal that is in development. Awardees of the RFA will work closely with each other and will deposit the data in the T1D portal.

Awards under this FOA will provide support for personnel, analyses, functional studies and other costs, as justified by the study design. An application may propose, for example, fine-mapping and sequencing of a targeted region(s), and/or functional validation to understand the biological impact of a genetic variant(s) at the levels of gene expression, protein function, cell and tissue functions, their upstream regulation, and/or their potential contribution to disease. Since different variants, i.e. common/rare or coding/non-coding, often require very different approaches to study them, this program will not be limited to any specific experimental approaches and the investigators are expected to employ the most amenable for the variants to be studied. For instance, variants in protein-coding region may involve characterization of protein product in vitro, in cell lines, or in transgenic animals. The interrogation of variants in non-coding regions may involve the analysis of sequence conservation, expression quantitative loci (eQTL), and chromatin modifications at regulatory sites. Applicants are strongly encouraged to seek multidisciplinary collaborations to ensure the inclusion of appropriate expertise for the proposed studies. Applications are expected to reflect integration of relevant groups such as clinicians, geneticists, basic cell biologists, computational scientists, systems biologists, statisticians and data scientists. Such an integrated effort will ensure that the complexities of phenotypic definition, the study design, the technical approaches, methods and model systems, the power and statistical genetic analysis are adequately considered.

Potential research areas, include but are not limited to:

• Human Studies: Functional validation studies should preferably use human DNA samples from phenotypically well-characterized individuals to correlate a gene variant with a phenotype and/or endophenotype.
• Comparison of wild type and gene variant functions: The molecular alteration associated with a gene variant frequently does not reveal whether the function of a gene is increased, decreased, or leads to unexpected functional consequences. Most genes have different levels of expression in different tissues. It is important to evaluate genetic changes in multiple cell types relevant to T1D. Approaches that can address these issues will help to identify the most promising molecular targets for therapeutic interventions to prevent and/or reverse T1D.
• Identification of causal genes/genetic variants: Studies exploiting genetic methodologies in concert with other methods, such as functional genomics, in silico mapping data, gene expression profiling, to identify causative genes or epigenetic/genetic variants and then unravel mechanisms of these genes are appropriate for this program announcement.
• Non-coding RNAs and regulatory elements: Studies to identify non-coding RNAs, transcription factors relevant to diabetes and relate function to genes/variants in non-coding RNAs, microRNAs, gene regulatory elements, gene copy number, or other putative non-protein coding regions of the genome are appropriate.
• Epigenetics and Epigenomics: Identification of cell type-specific epigenomic features associated with diabetes as well as functional validation of epigenetic mechanisms of gene regulation in the context of diabetes are relevant.
• Systems-level approaches: Bioinformatic resources (i.e., interactome, gene expression, epigenomic, proteomic, metabolomic, and anatomical databases) can be mined to generate testable hypotheses concerning the function of candidate genes and groups of genes and build a framework to understand the contribution of interacting networks based on causal effector transcripts to disease heterogeneity.
• Computational Approaches: Use of novel computational methods to integrate functional data and other data types to help to understand which variants are causal for a phenotype;
• Integrative analyses of multidimensional datasets such as genetics, genomics, transcriptomics, proteomics, metabolomics, and/or phenomics to identify key signatures, specific cell subsets, and/or biological pathways for further functional validation
• Animal studies/Model organisms: Animal studies and model organisms can be included, if they are complementary to the proposed human research and address mechanistic or therapeutic questions that cannot be addressed directly in humans.
• Limited Fine mapping and sequencing of a targeted human genomic region(s), including coding and non-coding;
• High Throughput approaches: The use of high-throughput approaches such as CRISPR modification of cell models for rapid phenotype screening and/or regulatory mapping

Below are types of projects that are not intended to be supported by this RFA:

• Clinical trials are not responsive to this FOA;
• Initial discovery Genome Wide Associated Studies (GWAS) or sequencing efforts;
• Simple replication of initial genomic findings.

The NIDDK remains interested in clinical trials and basic research in autoimmunity, and other topics related to our T1D mission. Please see our regular grant funding mechanisms (Parent R01) and collaborative opportunities with clinical networks such as Type 1 Diabetes TrialNet for funding opportunities in these areas.

All applicants are strongly encouraged to contact NIDDK program staff as soon as possible in the development of their application to discuss whether it would be considered responsive to this FOA.

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:

John F. Connaughton, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7797
Email: [email protected]

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

The following modifications also apply:

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

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 and responsiveness by NIDDK , NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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?

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?

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 the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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 NIDDK, 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.

Applications will be assigned

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 National Diabetes and Digestive and Kidney Diseases Advisory Council (NDDKAC).

. 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.

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.

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.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

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: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Beena Akolkar Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8812
Email: [email protected]

Ann A. Jerkins, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-2242
Email: [email protected]

Christina Coriz
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8848
Email: [email protected]

Section VIII. Other Information

This FOA is supported under the authority of P.L. 116-59, Continuing Appropriations Act, 2020, and Health Extenders Act of 2019; Section 1102. Diabetes Programs