Department of Health and Human Services


Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Funding Opportunity Title

Consortium on Beta-cell Death and Survival (HIRN-CBDS) (UC4)

Activity Code

UC4 High Impact Research and Research Infrastructure - Cooperative Agreement Programs

Announcement Type

New

Related Notices

  • November 27, 2013 - See Notice NOT-DK-14-007. Notice of Correction to Award Budget.

Funding Opportunity Announcement (FOA) Number

RFA-DK-13-018

Companion Funding Opportunity

RFA-DK-13-013, U01 Research Project – Cooperative Agreements
RFA-DK-13-014, U01 Research Project – Cooperative Agreements
RFA-DK-13-015, UC4 High Impact Research and Research Infrastructure - Cooperative Agreement Programs
RFA-DK-13-016, UC4 High Impact Research and Research Infrastructure - Cooperative Agreement Programs
RFA-DK-13-017, UC4 High Impact Research and Research Infrastructure - Cooperative Agreement Programs

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.847 

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) requests applications for a new research consortium, the Consortium on Beta cell Death and Survival (CBDS). The mission of CBDS will be to better define and detect the mechanisms of beta cell stress and destruction central to the development of T1D in humans, with the long-term goal of protecting the residual beta cell mass in T1D patients as early as possible in the disease process. CBDS will be part of the Human Islet Research Network (HIRN).

Key Dates
Posted Date

September 26, 2013

Open Date (Earliest Submission Date)

January 27, 2014

Letter of Intent Due Date(s)

January 27, 2014

Application Due Date(s)

February 27, 2014, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

June/July 2014

Advisory Council Review

October 2014

Earliest Start Date

December 2014

Expiration Date

February 28, 2014

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). 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.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description


Purpose

This Funding Opportunity Announcement (FOA) requests applications for a new research consortium, the Consortium on Beta cell Death and Survival (CBDS). The mission of CBDS will be to better define and detect the mechanisms of beta cell stress and destruction central to the development of T1D in humans, with the long-term goal of protecting the residual beta cell mass in T1D patients as early as possible in the disease process. The CBDS will be part of a collaborative research framework, the Human Islet Research Network (HIRN) that will include four research consortia and an Administrative Hub composed of a Bioinformatics Center and a Coordinating Center. HIRN's overall mission will be to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans.  In order to maximize scientific exchanges and accelerate research in that field, it is expected that all information, data, biomaterials, models, protocols, reagents, resources and methods developed by CBDS investigators will be shared not only within CBDS, but also with other HIRN investigators and with the research community. 

Background

The NIDDK Human Islet Research Network (HIRN)

Starting in 2014 NIDDK will establish a new team science program, the Human Islet Research Network (HIRN), to help organize and support collaborative translational research related to the loss of functional beta cell mass in Type 1 Diabetes (T1D). HIRN will be jointly supported by NIDDK and the type 1 diabetes special funding program, and its overall mission will be to better understand how human beta cells are lost in T1D, and to find innovative strategies to protect or replace functional beta cell mass in diabetic patients. This program will be configured as a modular network of small research consortia, each defined by a specific set of research priorities. The network structure will help to facilitate interactions between small communities of investigators organized around common biological and/or technological challenges, with the overall goal of developing innovative strategies for the treatment, prevention and monitoring of T1D.

HIRN will be initiated through issuance of six related funding opportunity announcements, and will use a Cooperative Agreement funding mechanism. Two complementary initiatives will provide the administrative structure needed to support HIRN activities through the creation of an Administrative Hub (HIRN-AH) composed of a Coordinating Center (HIRN-CC; RFA-DK-13-013) and a Bioinformatics Center (HIRN-BC; RFA-DK-13-014). Four independent research initiatives will invite four founding consortia, each supporting investigator-initiated projects in the following areas: Targeting and Regeneration (CTAR; RFA-DK-13-015), Human Islet Biomimetics (CHIB; RFA-DK-13-016), Modeling Autoimmune Interactions (CMAI; RFA-DK-13-017) and Beta Cell Death and Survival (CBDS; RFA-DK-13-018).

All HIRN research initiatives put a strong emphasis on human disease biology, the use of human cells and tissues, and the development of reagents, tools and disease-modeling platforms that can help further our understanding of the human disease process, or lead to innovative treatment strategies for patients with severely depleted beta cell mass. Beyond the set of six founding FOAs issued in 2014, it is anticipated that additional HIRN initiatives may be issued in future years, provided availability of funds, to support the evolution of the program over time, and in response to emerging scientific and technological advances.

Consortium on Beta-cell Death and Survival (HIRN-CBDS)

Type 1 Diabetes (T1D) is a progressive immune-mediated disease that is preceded by an asymptomatic preclinical period of highly variable duration in humans. In addition to genetic susceptibility, it is believed that biological or environmental triggers contribute to the initiation and development of T1D, leading to the progressive disappearance of functional beta cells from the pancreatic islet, and to the development of an autoimmune response targeting specifically and exclusively insulin-producing beta cells.

Understanding beta cell dysfunction and beta cell loss during the period of asymptomatic or "silent" T1D that takes place in genetically susceptible individuals, with or without multiple T1D autoantibodies, may provide critical insight into the respective contribution of metabolic stress, inflammation or other pathogenic processes to beta cell injury, and ultimately to the development of autoimmune T1D. A more thorough mechanistic understanding of these early steps could lead to novel therapeutic solutions to protect and renew the population of residual beta cells present in recent-onset T1D patients. Moreover, the development of a new generation of highly-sensitive, highly-specific biomarkers that can reliably report on the subtle changes in beta cell stress, damage or death during the asymptomatic period could lead to early therapeutic interventions in at-risk individuals that delay or even prevent the development of autoimmunity.

T1D is a difficult disorder to investigate, given the absence of reliable methods for early detection, the heterogeneity of the human disease, and the lack of access to the target organ in living individuals. Historically, investigations have either examined indirect features of the disease in patients with T1D, or used animal models to dissect pathogenic mechanisms. In that respect, the non-obese diabetic (NOD) mouse has been used effectively to formulate hypotheses regarding disease onset and progression. However, recent studies using cadaveric human pancreata are pointing to important differences between mice and humans with respect to the mechanisms underlying the loss of beta cells in early T1D. Most of these pioneering studies have used pancreatic specimens collected by the Network for Pancreatic Organ Donors with Diabetes (nPOD) that was established to recover and characterize pancreata and related organs from donors with various risk levels for type 1 diabetes (T1D), including donors with recent disease onset and asymptomatic donors with T1D autoantibodies. The pathological analyses of these tissues point to unique characteristics of the human pancreas at disease onset, including decreased pancreatic size and exocrine atrophy; paucity or absence of insulitis; lobular loss of beta cells in pancreatic regions where insulitis does exist; diminished insulin content in remaining beta cells; and heterogeneity of the pancreatic pathological profile between organ donors. Altogether, these observations suggest that multiple mechanisms may lead to the loss of functional beta cells and contribute to the pathogenesis of T1D in humans.

An early and reliable identification of individuals who are entering asymptomatic T1D would greatly facilitate the study of the initial phase of the disease and the development of therapeutic strategies to stop the progression towards autoimmunity. At present, the detection of multiple autoantibodies is the best biomarker of T1D risk, but it also provides proof that the autoimmune process is already floridly active. For that very reason, even the discovery of new antibodies against other native islet epitopes (autoantigens) is unlikely to yield biomarkers that report on the initiation of the disease process. However, recent studies in stressed islets (mouse and human) have identified defects in the beta cell transcriptional and translational machineries that could provide highly-specific biomarkers of early T1D. Beta cell stress causes the formation of many specific or deficient cell products, including miRNAs; abnormally spliced mRNAs resulting in modified protein isoforms; inappropriately folded, cleaved or posttranslationally-modified native proteins; and aberrant products resulting from dysfunctional ER-associated degradation pathways. Some of these modified peptides and proteins can be turned into neo-antigens that are specific of early beta cell injury, and may prime the autoimmune process in T1D. miRNA patterns in human diseases are often tissue-specific, and miRNAS display unusually high stability in formalin-fixed tissues as well as in plasma, serum and saliva, and are easy to detect with a high degree of specificity. The release in the bloodstream of some of these beta cell stress-induced products, or the generation of antibodies against neo-antigens of the stressed beta cell, may constitute highly-specific biomarkers of the earliest events leading to T1D.

Based on recent developments in islet biology research, several assumptions about early stages of the disease process in humans may have to be revisited. For example, it is still widely accepted that the reduction of functional beta cell mass in T1D results from a massive beta cell destruction that starts during the asymptomatic phase. But other mechanisms may contribute to the progressive "disappearance" of functioning beta cells in the islets of patients with T1D, at least in the early stages. Recent studies on islet plasticity indicate that beta cell stress and dysfunction can result in the dedifferentiation of mature beta cells into "progenitor-like" cells. The relative contribution of a variety of mechanisms (apoptosis, necrosis, autophagy, de-differentiation, autoimmune destruction) to the reduction in beta cell number during the asymptomatic phase, and the contribution of the various cell types present in the pancreatic compartment (such as cells of exocrine, endocrine, neuronal or immune origin) to the early disappearance of beta cells, need to be explored anew in the context of human pathology. In that regard, the tissue heterogeneity that characterizes many human pancreata around the time of clinical presentation represent a rich experimental opportunity, since islets where the beta cells have disappeared, islets where beta cells are being eliminated, and islets where beta cells are still intact are often found together within a single biopsy.

CBDS will encourage the use of human pancreata and related tissues with the goal of providing a definition of the pathogenic mechanisms leading to the demise of beta cells in patients with T1D. It is expected that this information will assist in the development of improved biomarkers for the asymptomatic phase of human T1D. CBDS will also support the development of new technologies and methods that will help investigators extract complex biological information from unfavorable material such as paraffin-embedded or frozen tissues obtained from cadaveric donors, to help answer fundamental questions about the early stages of human T1D.

HIRN-CBDS: Research Objectives and Scope

The exploration of the specific events responsible for beta cell failure and destruction at the onset of human T1D has been hampered by the lack of two important sets of tools:

Contributions relevant to this initiative are therefore restricted to the following two areas of research:

1) Development of specific biomarkers of human beta cell stress or beta cell death in asymptomatic T1D:

Most discoveries to find non-invasive biomarkers of beta cell stress or beta cell death involve the use of omics-based screens to look for bio-products that vary significantly between samples taken from Type 1 diabetic and control subjects, or between samples taken at different stages of T1D progression in individual patients. But as noted above, the asymptomatic phase of T1D in humans is characterized by slowly developing and relatively subtle changes, such as the stress or destruction of only a subset of beta cells in only a subset of pancreatic islets at any given point in time. These biological events may be relatively insignificant in the context of all other physiological changes occurring daily in the human body, and are therefore unlikely to leave strong biological signatures that can be detected using standard approaches that rely on global molecular analysis of body fluids or of the whole pancreatic tissue.

A more promising strategy may be to identify molecular signatures or cell-processed products that are highly-specific of beta cell identity or beta-cell stress, and to look for their presence in the body fluids (blood, urine, saliva) of individuals who are either at-risk or newly-diagnosed. Relevant biomarkers may include epigenetically-modified genomic DNA regions that are released in the blood stream by dying beta cells; mechanistically informative modified products (such as proteins, peptides, nucleic acids) secreted or excreted by stressed beta-cells; circulating free or exosome-encapsulated microRNAs specifically released by stressed beta cells; or antibodies against rare neo-antigens created as a result of early beta cell stress or injury early in the disease process. This initiative will support the identification and validation of such biomarkers in human samples, and the development of related detection assays that can be used safely in humans. Relevant applications need to propose the development of biomarkers and assays that can detect human beta cell stress, injury or death non-invasively, in a quantitative, specific and sensitive manner, to such a degree that they provide an accurate and reliable prediction of the progression to autoimmunity in asymptomatic at-risk individuals.

2) Development of tools for the exploration of islet heterogeneity, stress and plasticity in human pancreata:

Given the recent availability of high-quality collections of pancreata from cadaveric organ donors, investigators interested in studying T1D natural history and pathogenesis have not yet had the opportunity to develop sophisticated analytical tools to extract meaningful biological information from challenging biospecimens such as frozen or paraffin-embedded tissue slices. In other areas of biology however, such as cancer or brain research, many of these technologies are being developed, and could be applied or modified to study archived human pancreata. For example, laser-guided microdissection protocols allow the recovery of just a few selected cells from minute amounts of tissues. The dissected cells can then be used for a variety of investigations such as transcriptomic, epigenomic, proteomic or metabolomic studies, as well as T-cell epitope mapping, using technologies such as whole exosome sequencing, pathology tissue chromatin immunoprecipitation (PAT-ChIP), ion semiconductor sequencing (ISS), matrix-assisted laser desorption/ionization (MALDI), combinatorial peptide-MHC multimer staining and mass cytometry and single-cell omics analyses. Other type of analyses such as multiplexed fluorescence microscopy allow for the quantitative characterization of dozens of analytes simultaneously (including peptides, proteins and nucleic acids), with single-cell and subcellular definition, and across the entire tissue.

This initiative will support the development or adaptation of emerging technologies for the biological and molecular exploration of archived human pancreata. It will also support the use of these advanced tools to answer key biological questions related to the development of T1D such as: do beta cells contribute to their own destruction/disappearance and if so, how? Does beta cell stress occur at different stages of human T1D and if so, does it result in specific molecular signatures? Does beta cell stress initiate or perpetuate autoimmunity? Does beta cell de-differentiation occur in human T1D and if so, does it contribute to resolve beta cell stress? Why are some islets spared from insulitis in the pancreata of so many T1D patients? What is the contribution of the various islet cell types to disease progression before, during and after insulitis? Is the exocrine pancreas involved in islet invasion? Does beta cell regeneration occur in concert with beta cell destruction in subjects with islet autoimmunity? Can other islet cells contribute to a replenishment of the beta cell mass once the inflammation has subsided? What are the specific characteristics of the residual pools of beta cells found in many patients with long-term T1D? Can specific epigenetic signatures be used in the context of fixed human pancreata to identify sub-populations of islet cells that are phenotypically identical, but may result from distinct lineage histories and may contribute differently to the disease process? Can single-cell sequencing and single-cell proteomics allow the functional states of individual islet cells to be analyzed, help uncover cell lineage relationships, or lead to the discovery of early biomarkers of beta cell stress and injury? Can post-translational modification of autoantigens in stressed beta cells allow autoreactive T-cells to escape immune tolerance, thereby priming the autoimmune process?

The use of animal models in combination with the study of human samples, such as lineage tracing experiments in the NOD mouse or xenograft models using transplanted human islets or tissues, may be required in order to achieve some of the goals described in this initiative, and will be permitted. However, applications proposing to perform primarily mechanistic studies in the mouse, with only a few validation experiments in human tissues, will not be considered responsive to this announcement and will not be reviewed.

In choosing a source of human biospecimens, applicants are encouraged to use high-quality repositories, biobanks and procurement networks, whether they are linked to NIDDK-funded clinical studies such as the Diabetes Prevention Trial-Type 1 (DPT-1) or the Type 1 Diabetes Trialnet (https://www.niddkrepository.org/niddk/home.do ), or supported by private research efforts such as the JDRF nPOD (http://www.jdrfnpod.org/ ) or the T1D Exchange (http://www.t1dexchange.org/ ). If available, pancreata that are either densely genotyped (such as from NIH-supported the GTEx collection: https://commonfund.nih.gov/GTEx/overview.aspx ) or originating from donors with well-documented disease history or health records, should be used. 

Applicants may decide to address one or both of the two priority areas described above. The assembly of multidisciplinary teams under a single application to address the scientific challenges outlined in this initiative is encouraged, particularly if they combine different expertise (such as beta cell biology, immunology, experience with state-of-the-art analytical tools or technologies). But single-investigator applications from individuals with the required expertise to make a major contribution are also welcome. Regardless of the team-structure and composition of the initial UC4 application, all CBDS investigators will be expected to work collaboratively with all of their CBDS and HIRN colleagues and to contribute to an environment of sharing and trust across the network.

All methods, reagents, resources, biomaterials, protocols, data and models developed by CBDS investigators are expected to be made available to the research community. Because the individual UC4 projects will be coordinated through CBDS, the timeline and processes for sharing within CBDS and with the community at large will be established by the CBDS NIDDK Project Scientist or the CBDS Steering Committee. All participants will be expected to adhere to these policies as a term of the award. Policy documents for CBDS will be accessible on the HIRN website.   

Meetings of CBDS and HIRN

CBDS Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))  must participate in an initial in person HIRN meeting soon after awards are made, in the annual HIRN Investigator Scientific Retreat, as well as in CBDS Steering Committee teleconferences to be held at least bi-annually.  All participants will be obligated to abide by the policies adopted the majority vote of the CBDS Steering Committee.  In the application, research project budget requests must include costs for the PD/PI and up to two other members of the individual project to attend both the initial in-person HIRN meeting and the annual HIRN Investigator Scientific Retreat. The annual HIRN Investigator Scientific Retreat will last 2-3 days.  All CBDS teleconferences will be organized and administered by the HIRN-CC to coordinate the research projects to be conducted by the research grantees.  Note that the HIRN-CC will support costs of all CBDS and HIRN-related meetings except for costs for research project investigators to travel and attend the meetings. The HIRN-CC is also responsible for providing and maintaining a record of minutes of all CBDS meetings, which will be approved by the CBDS Steering Committee.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIDDK intends to commit $9 million to fund 2-4 awards in FY2014.

Award Budget

Application budgets are limited to $600,000 per year in direct costs. This limit is inclusive of any direct and F&A costs associated with consortium or subcontract agreements.

Award Project Period

The maximum project period is five years. 

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

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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.

Required Registrations

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.

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

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

Eligible Individuals (Program Director/Principal Investigator)

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

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

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Section IV. Application and Submission Information


1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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:

The letter of intent, preferably electronically, should be sent to:

Francisco O. Calvo, Ph.D.
National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK)
6707 Democracy Boulevard, Room 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: 301-594-8897
Email: calvof@mail.nih.gov

Page Limitations

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

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

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. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). 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.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. 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.

Since these awards will be issued with a 5-year budget and project period from the same fiscal year, the grantee will not have any authority for an automatic extension nor will one be permitted with NIH prior approval. Funds will not be available for expenditure beyond September 30 of the 5th fiscal year after the period of availability. Thus, extensions of the budget/project period will not be allowed.

6. 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 Applying Electronically.

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 by the Center for Scientific Review and responsiveness by NIDDK, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at calvof@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Post Submission Materials

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

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

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

Scored Review Criteria

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

Significance

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

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do PD(s)/PI(s) provide evidence of experience working productively in collaborative environments? Do PD(s)/PI(s) provide documented evidence of experience sharing data and reagents with the research community?  

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? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?  

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?   

Additional Review Criteria

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

Collaborative Research Opportunities: 

Does the project present an opportunity for research that would be enhanced by consortium interaction, collaboration and expertise?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

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) Genome Wide Association Studies (GWAS)..

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications:

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA. .

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. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information


1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement UC4, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have the Primary Responsibility for:

NIH Staff have Substantial Programmatic Involvement that is above and beyond the normal stewardship role in awards, as described below:

Areas of Joint Responsibility include:

Through the Awardees and NIH staff, CBDS will cooperatively develop and implement processes to submit information and data to the HIRN-AH, determine criteria and processes for quality control of information and data to be posted for the research community, refine scientific objectives, and implement research advances to facilitate the goals of the study, consistent with NIH policies and achieving the goals of the program as described in the Funding Opportunity Announcement. There will be an initial face-to-face meeting of HIRN and a minimum of 2 CBDS meetings (teleconferences or face-to face meetings) annually. CBDS awardees, the CBDS Project Scientist, and the CBDS Program Official are expected to attend these meetings. One of these bi-annual meetings could be combined with the annual HIRN Investigator Scientific Retreat.

Steering Committee

CBDS awardees agree to the governance of the CBDS through a Steering Committee.

HIRN Trans-Network Committee (HIRN-TNC)

The HIRN-TNC will consist of: the PD/PI of the HIRN CC, the PD/PI of the HIRN BC, and the Steering Committee Chairs and Project Scientists of the HIRN scientific topic consortia (CHIB, CTAR, CMAI, and CBDS); the TNC is not a governing body and does not cast votes.

Expert Scientific Panel (ESP)

An independent panel of 2-5 External Experts will be appointed by the NIDDK and meet by teleconference with the CBDS Project Scientist and the CBDS Project Officer at least once a year. The CBDS-ESP will be updated on progress and give feedback to NIH on adjustments and future directions for the CBDS research projects. On an annual basis, and following input from the ESP members, NIDDK staff will appoint an ESP Chair who will be required to attend the annual HIRN Investigator Scientific Retreat, to participate to the CBDS Steering Committee meetings as ex-officio, and to serve as the CBDS-ESP representative to the larger HIRN-ESP that will also meet once a year. The CBDS-ESP Chair will be tasked with relaying the CBDS Steering Committee recommendations for new Opportunity Funds Initiatives to the HIRN-ESP. All CBDS-ESP members will also be invited to listen as ex-officio to CBDS Steering Committee meetings. Members of the CBDS-ESP may be asked, on an ad hoc basis, in the peer review of applications for new research applications that request “opportunity pool” funds. The HIRN-CC will support costs for teleconferences between the ESP and the CBDS Steering Committee, will arrange the CBDS-ESP and HIRN-ESP teleconferences, maintain a record of minutes, and support costs for the CBDS-ESP chair to participate in the annual HIRN Investigator Scientific Retreat.

Dispute Resolution   

Disagreements that may arise in scientific/technical matter or programmatic matters (within the scope of the award) between award recipients and the NIDDK may be brought to arbitration after first attempting to resolve the issue through the Steering Committee or its subcommittees, as appropriate.  An Arbitration Panel composed of three members will be convened.  It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee.  This special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

3. Reporting

Progress reports for multi-year funded awards are due annually on or before the anniversary of the budget/project period start date of award. The reporting period for multi-year funded award progress report is the calendar year preceding the anniversary date of the award. Information on the content of the progress report and instructions on how to submit the report are posted at http://grants.nih.gov/grants/policy/myf.htm

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Olivier Blondel, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: (301) 451-7334
Email: blondelol@niddk.nih.gov

Peer Review Contact(s)

Francisco O. Calvo, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: (301) 594-8897
Email: calvof@mail.nih.gov

Financial/Grants Management Contact(s)

Todd Le
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: (301) 594-7794
Email: toddle@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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