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.

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

Purpose

This Funding Opportunity Announcement (FOA) requests applications for the adaptation of medium- to high-throughput omics technologies with single cell- or near single cell-resolution to archived human pancreatic tissues to facilitate the exploration of the molecular and cellular events responsible for beta cell failure and/or destruction at the onset of T1D. Successful applicants will join the Consortium on Beta cell Death and Survival (CBDS), whose mission is 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, and preventing the progression to autoimmunity. The CBDS is part of a collaborative research framework, the Human Islet Research Network (HIRN), that includes four research consortia and an Administrative Hub composed of a Bioinformatics Center and a Coordinating Center. HIRN's overall mission is 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.

The NIDDK Human Islet Research Network (HIRN)

Starting in the fall of 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 is being initiated through the creation of four research 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). HIRN research activities will be facilitated by 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).

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.

Exploring the asymptomatic phase of human T1D

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.

The cellular and molecular events taking place in the pancreatic islet during the asymptomatic phase of human T1D are very difficult to investigate, given the absence of reliable methods for early detection in humans, the heterogeneity of the human disease, and the lack of access to the target organ in living individuals. More generally, the development, functional maturation and fine cellular organization of the human pancreas, and how its specific structure and organizational principles contribute to initiation of the disease, are still largely unknown. Historically, investigations have either examined indirect features of the disease in patients with early 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 pancreatic tissues 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, and that 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.

Single Cell Analysis tools for the human pancreas

The exploration of the cellular and molecular events responsible for beta cell failure and destruction at the onset of human T1D has been hampered by our lack of detailed and specific knowledge of the human pancreas developmental and functional organization, and by the lack of methods to visualize cell and signaling interactions in fixed pancreatic tissues from organ donors. Particularly needed are technologies that can provide detailed and integrated molecular analyses of human pancreata at the cellular and sub-cellular level, to include specific molecular signatures, metabolic profiles and the activation of disease pathways in the subsets of islets cells that are contributing to the initiation of the disease process in asymptomatic human T1D. Of particular interest are technologies with a working scale of resolution that spans the range from whole organ to subcellular details.

In recent years, several technologies and tissue preparation approaches have enabled investigators to perform transcriptomics, proteomics and metabolomics measurements and analyses on fixed tissues with single cell- or near single cell resolution. Examples of such technologies include, but are not limited to:

• Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) that can be used to map the spatial distribution of a large number of analytes simultaneously, including proteins, peptides and metabolites;
• Single-cell in situ RNA profiling by sequential hybridization and sequential barcoding FISH (seqFISH), that allows multiplex detection of the mRNAs of hundreds of genes simultaneously with single molecule resolution in situ in organ slices;
• Combination of padlock probes with in situ proximity ligation assay, that allows the measurement of relative mRNA and protein expression levels, and the detection of protein modifications or protein complex formation;
• CLARITY, a method for chemical transformation of intact biological tissues into a hydrogel-tissue hybrid, which becomes amenable to proteomics or transcriptomics interrogation with macromolecular labels while retaining fine structure and native biological molecules.

This FOA encourages the adaptation of medium- to high-throughput omics technologies that provide single cell- or near single cell-resolution to the exploration of the human pancreas, with the ultimate goal of extracting complex biological information from paraffin-embedded or frozen tissues obtained from cadaveric donors in order to help answer fundamental questions about the cellular and functional organization of the human pancreas, the early cellular and molecular events leading to T1D in humans, and to assist in the discovery of biomarkers specific for the asymptomatic phase of human T1D. Applications should be structured as collaborations between (at least) one expert in single cell-resolution omics technologies and (at least) one pancreatic islet biologist, and should include the following two elements:

• Technology Development: Applicants must propose to apply to human pancreatic tissues at least one technology that can provide quantitative, medium- to high-throughput "omics" measurements with single cell- or near single cell-resolution in fixed tissues. While in the early stages of technology development the application of the method to the pancreas may require the use of non-human tissues (such as mouse), application of the proposed technology to archived human pancreata should start no later than the second year of funding;
  
  
• Application of the technology to a HIRN-relevant Biological Paradigm: Applicant must propose to use the technology to answer a biological question relevant to the mission of CBDS or HIRN. Examples of biological paradigms that the new technology may help explore include, but are not limited to:
  • Specificity of human pancreas development, maturation, cellular and functional organization, plasticity and early T1D pathogenesis as compared to similar principles described in rodent models;
• Contribution of the various islet and immune cell subtypes to disease initiation and progression before, during and after insulitis;
• Discovery of highly-specific molecular signatures of early T1D, such as expression of rare transcripts or posttranslational protein modifications, that can be used as early biomarkers of disease;
• Exploration of various aspects of beta cell stress or injury that may contribute to the initiation of T1D in humans, and identification of related molecular signatures;
• Exploration of islet cell diversity and plasticity in the human pancreas, including identification of distinct beta cell subtypes;
• Exploration of possible beta cell dedifferentiation or trans-endocrine fate switching mechanisms, and their contribution to the disease process;
• Role of the exocrine pancreas in islet invasion and/or other aspects of the disease process;

In choosing a source of human biospecimens, applicants are encouraged to use recognized repositories, biobanks or procurement networks that have well-documented tissue collections. For example, the JDRF-supported Network for Pancreatic Organ Donors with Diabetes (nPOD, http://www.jdrfnpod.org/ ) is a resource specifically devoted to obtaining biospecimens from T1D diabetic donors at different stages of the disease, as well as from asymptomatic donors with T1D autoantibodies. When available, pancreata that are either densely genotyped (such as from the NIH-supported Genotype-Tissue Expression GTEx collection: https://commonfund.nih.gov/GTEx/overview.aspx ) or originating from donors with well-documented disease history or health records, should be used. When the use of tissues from independent procurement sources is proposed, the origin and quality of the biospecimens should be clearly described in the application.

Successful applicants 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.

CBDS Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must participate 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. 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.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

Applicants 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.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. 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.

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, preferably electronically, should be sent to:

Francisco Calvo, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: 301-594-8897
Email: [email protected]

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

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

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

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

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

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

• PDs/PIs should provide evidence of prior experience working productively in collaborative programs.

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

• Budget requests must include costs for the PD/PI and up to two other members of the individual project to attend the annual HIRN Investigator's Scientific Retreat.

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

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

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 modifications:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication. Investigators responding to this funding opportunity are expected to include a resource sharing plan addressing how unique research resources will be shared or explain why sharing is not possible.
• Applicants should discuss the following:
  • Availability of biological resources utilized and/or developed (mouse models, cell lines, reporter systems, vectors, molecules, antibodies, biomarkers, etc.);
  • Availability of technologies and protocols developed with funds from this award.

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

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

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

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.

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.

This initiative is not subject to intergovernmental review.

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

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

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.

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, NIH. Applications that are incomplete will not be reviewed.

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

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

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

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

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

Significance

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

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?

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 human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

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

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.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

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.

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:

• 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.

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 (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.

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

The administrative and funding instrument used for this program will be the cooperative agreement 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:

• The awardee will be primarily responsible for defining the objectives and approaches, planning, conduct, analysis, and publication of results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award.
• The Program Director/Principal Investigator will assume responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research supported under this Funding Opportunity Announcement in accordance with the terms and conditions of award, as well as all pertinent laws, regulations and policies.
• The awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current HHS, PHS, and NIH policies.
• All staff of the Awardee will maintain the confidentiality of the information developed by the investigations, including, without limitation, study protocols, data analysis, conclusions, etc. per policies approved by the consortium as well as any confidential information received by third party collaborators.
• Awardees must analyze, publish and/or publicly release and disseminate results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIH, consistent with NIH policies and goals of the FOA.
• All staff of the Awardee will be required to participate in a cooperative and interactive manner with NIH staff, one another and with the HIRN-AH in all aspects of CBDS.
• Awardees are expected to share data, materials, models, methods, information and unique research resources that are generated by the projects in accordance with CBDS policies in order to facilitate progress. When appropriate, and in accordance with NIH policies, awardees will be expected to collaborate; share novel reagents, biomaterials, methods and models and resources; and share both positive and negative results that would help guide the research activities of other CBDS members.
• Awardees will submit a list of milestones and project deliverables to the HIRN CC prior to the initial HIRN meeting, and will update this list annually.
• CBDS Awardees agree to establish agreements amongst themselves that address the following issues: (1) procedures for data sharing among consortium members and data sharing with industry partners as appropriate; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biospecimens under an overarching MTA amongst consortium members that operationalizes material transfer in an efficient and expeditious manner; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• Awardees agree that industry collaborations should be governed by a research collaboration agreement (e.g. CTA, RCA, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures and any policies and procedures developed by the CBDS.
• Awardees must operate in accordance with processes and goals as delineated in the Funding Opportunity Announcement.
• Upon completion or termination of the research project(s), the awardees are responsible for making all study materials and procedures broadly available (e.g., putting into the public domain) or making them accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The data sharing plan should include a plan to accomplish this at the end of the study.
• Awardees may be asked by NIH staff to scientifically review applications for special opportunity pool funds, as deemed appropriate.

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

• The NIDDK will designate program staff, including a Program Officer and a Grants Management Specialist to provide stewardship and administrative oversight of the cooperative agreement. The Program Officer and Grants Management Specialist will be named in the Notice of Grant Award.
• The NIH will invite experts with relevant scientific expertise to provide feedback to the NIH on CBDS activities. The External Experts will meet to review the progress of the research projects and to advise NIH staff of scientific developments and opportunities that may enhance the achievement of the study goals.
• An NIDDK Project Scientist will be substantially involved in this project above and beyond the normal stewardship of an NIDDK Program Official as follows:
• The NIH Project Scientist will coordinate and facilitate the research projects, attend and participate in all meetings of the CBDS, and act as a liaison between the Awardee and the External Experts.
• The NIH Project Scientist and Program Officer will review the scientific progress, cooperation in carrying out research, and maintenance of high quality research in each of the individual research project, and review the project for compliance with operating policies developed by the CBDS. Based on this review, the Project Scientist in conjunction with the Program Officer may recommend to the NIH to continue funding, or to withhold or restrict support for lack of scientific progress or failure to adhere to policies established by the CBDS. Review of progress may include regular communications between the Program Director/Principal Investigator and NIH staff, periodic site visits for discussions with awardee research teams, fiscal review, and other relevant matters. The NIH retains the option of organizing periodic external review of progress.
• The NIDDK reserves the right to terminate or curtail any study or any individual award in the event of (1) substantial shortfall in data collection or submission, quality control, or other major breach or a study protocol or CBDS policy and procedure, (2) substantive changes in a study protocol that are not in keeping with the objectives of the FOA, and/or (3) concerns related to human subject safety that prompt the need for premature termination.
• The NIH Program Scientist and Program Officer will review applications for Special Opportunity Funds for responsiveness to program goals to insure that they are within the scope of CBDS research as described in the Funding Opportunity Announcement and NIH guidelines. The NIH will enlist additional scientific consultants as necessary from within the NIH whose function will be to assist the Project Scientist in carrying out the goals and aims of the approved studies. The NIH will have one vote for any key committees, regardless of the number of NIH consultants involved in the project.
• The NIH Project Scientist will have substantial scientific programmatic involvement in research coordination and performance monitoring. The dominant role and primary responsibility for these activities resides with the awardee, however, specific tasks and activities in carrying out the studies will be shared among the awardees and the NIH Project Scientist.
• The NIH Project Scientist serves as a resource with respect to other ongoing NIH activities that may be relevant to CBDS studies to facilitate compatibility and avoid unnecessary duplication of effort.
• The NIH Project Scientist or designee may coordinate activities among awardees by assisting in the design, development, and coordination of a common research protocol and statistical evaluations of data and in the publication of results.
• The NIH Project Scientist may review procedures for assessing data quality and monitor study performance.
• The NIH Project Scientist may be a co-author on study publications. In general, to warrant co-authorship, the NIH staff must have contributed to one or more of the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.

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.

• On an annual basis, and following input from the CBDS Steering Committee members, NIDDK staff will appoint a Steering Committee Chair who will be in charge of facilitating the CBDS Steering Committee meetings and teleconferences. In collaboration with the HIRN-CC and the NIH Project Scientist, the Chairperson is responsible for coordinating the Steering Committee activities, for preparing meeting agendas and for chairing meetings.
• The Steering Committee, including the Project Scientist, is responsible for establishing and implementing processes and criteria for recommending special projects for consideration for special opportunity funds by NIH staff.
• The NIH Project Scientist may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees.
• The Steering Committee will be composed of the Program Director/Principal Investigators for each UC4, or by UC4 representatives (one per UC4 grant) chosen by the Program Director/Principal Investigators in the cases of multi-PI grants, and the NIH Project Scientist. Only the UC4 PI/PD or multi-PI UC4 representatives and the NIH Project Scientist will be voting members of the Steering Committee and will attend all meetings of the Steering Committee. Each full member will have one vote. Other designated NIH program staff attending the steering committee meetings will be ex officio (non-voting) members. The CBDS Steering Committee will meet at least twice a year.
• All major scientific and policy decisions will be determined by voting policies as established by the Steering Committee at the initial meeting. This committee will operate to develop collaborative protocols, identify impediments to success and strategies to overcome them, develop shared tools for disseminating information about the projects, and identify opportunities for sharing techniques, materials, information and tools developed within each individual project as appropriate. Steering Committee activities and decisions will consider the advice of the External Experts.
• The NIH Project Scientist will help the Steering Committee develop and draft operating policies.
• NIDDK staff, in concert with the Steering Committee, will have the option to redirect research activities being pursued within the UC4 grants if it is considered beneficial to the overall program.
• The awardee will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the Steering Committee and Subcommittees.
• Awardees must serve on CBDS subcommittees as needed. Subcommittees will report progress at Steering Committee Meetings and/or lead discussions at the Annual Investigator’s Retreat.

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.

• The TNC will facilitate communication and foster collaboration across the different consortia.
• The TNC will be responsible for organizing the yearly HIRN Scientific Investigator’s Retreat.
• The TNC will meet by teleconference at least twice a year and will be organized by the HIRN CC. Meetings will be used to discuss and prioritize, and review the progress of applications that will use "opportunity pool" funds. Subcommittees of HIRN, as well as working groups for scientific planning may be established and require participation by the CBDS members through in-person, electronic, or teleconference meetings, as appropriate. The HIRN CC is responsible for providing and maintaining a record of minutes of all EC meetings, which will be approved by the EC.

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.

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.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

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

Olivier Blondel, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-7334
Email: [email protected]

Francisco Calvo, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8897
Email: [email protected]

Todd Le
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7794
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. This FOA is supported under a Special Statutory Program for Type 1 Diabetes Research via PL 113-93 (Section 204), "The Protecting Access to Medicare Act of 2014.