It is critical that applicants follow the Research (R) 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

NIDDK requests applications to join a new research consortium, "Microphysiological Systems (MPS) for Modeling Diabetes" or MPS-MOD. NIDDK will support the development and validation of human tissue chips that closely mimic the normal physiology of the pancreatic islet, liver, skeletal muscle and white adipose tissue (WAT) that when combined with relevant immune components, will be sufficient to model inflammatory drivers of metabolic dysfunction. Ultimately, the goal is to combine the human metabolically active tissue chips with immune system components to develop a fully integrated model of immune-mediated metabolic dysfunction, as a first step towards the generation of in vitro models for human type 2 diabetes and other metabolic diseases. The consortium will lay the groundwork for establishing reproducible and translatable microphysiological platforms that are capable of modeling key aspects of type 2 diabetes pathophysiology, that may ultimately be used for preclinical efficacy studies. These models should be validated through the testing of known diabetes therapeutic agents and biomarkers, using best practices and rigorous study design. The need for high-quality well-characterized isogenic/patient-derived iPSC lines and standardized differentiation procedures is a critical step in turning disease-specific iPSCs into tools for discovery. In the future, iPSC-based human tissue chips could play a central role in drug development, testing, screening, drug repurposing, and toxicity testing. Eventually, collections of iPSCs that capture the heterogeneity of T2D could be used to conduct "clinical trials in a dish" and to discover biomarkers of response. An essential feature will be a multidisciplinary approach that brings together basic science experts and physician scientist in stem cell biology, bioengineering, computational biology, pharmacology, immunology, liver biology, islet biology, adipose biology, metabolism and diabetes.

Funds from the NIDDK will be made available through the UG3/UH3 cooperative agreement award mechanism. The UG3 phase will support studies to develop and validate in vitro models combining tissue chip technologies with human islet, liver, skeletal muscle, WAT and immune components derived from an iPSC cell source. The UG3 phase should include sensitive on-chip assays that measure normal metabolic function. The UG3/UH3 phases should use primary human tissues to help characterize both the maturity and adult function of iPSC-derived tissues, and by the end of the UG3 period, should have significant progress towards generating at least two multicellular liver, islet, skeletal muscle and/or WAT chips, all using an iPSC cell source. The UH3 phase will support studies to improve and validate the individual tissue chips and on-chip assays, add immune elements, and to physically integrate the chips with each other. Features that are essential for the development of models of insulin resistance/inflammation/type 2 diabetes should be included. A UG3 project that meets its milestones will be administratively considered by the NIDDK and other participating ICs and prioritized for transition to the UH3 award. Applicants responding to this FOA must address objectives for both the UG3 and UH3 phases.

Background

Currently, in diabetes research, in vivo animal models serve as gold standards for advancement to clinical trials, but the drawbacks associated with such models are major contributors to the costs and uncertainties in therapy development. Because of the interspecies differences, animal models often fail to recapitulate many aspects of human physiology. To address these concerns, NIDDK has identified a critical need to develop new pre-clinical model systems to study normal human physiology and metabolism of the pancreatic islet, and, in 2014, created the Consortium on Human Islet Biomimetics (CHIB) https://hirnetwork.org/consortium/chib. CHIB’s goals are to derive a bioengineered human islet that can maintain a functional, healthy adult human beta cell phenotype for a period of up to 4 weeks, in vitro. The CHIB teams are working to build a pancreatic biomimetic that combines several salient features: cadaveric human islets or islets created from a human pluripotent stem cell source, 3D cytoarchitecture, and recreation of a human islet niche with integrated vasculature, ECM, innervation and/or soluble factors.

Remaining Challenges facing MPS-based diabetes modeling:

Human pancreas: Producing an appropriately engineered platform that both recapitulates the microenvironment of the islet, and better mimics the complex structure and physiology of the islet, are important features for maintaining pancreatic beta cell health. The development of robust, reproducible, and sensitive methods of on-chip monitoring of islet function (such as dynamic insulin secretion has proven challenging and is an ongoing research activity in CHIB. Although the human islet biomimetic effort is well underway, a remaining challenge will be to develop efficient and reproducible protocols to generate and combine the different cellular subtypes of the islet (such as alpha cells secreting glucagon). Incorporating islet vasculature, and other cellular components of the niche using an isogenic iPSC cell source, and addressing on-chip oxygen demand is also critical.

Human liver: Recent advances have demonstrated the feasibility of generating vascularized and complex liver buds (ex-vivo) by combining cells generated from multiple human cell sources, including iPSC derivatives. However, a major drawback to the liver chips generated from an iPSC cell source, is that these liver organoids are fetal-like in nature, and do not fully re-capitulate adult function, in vitro. Furthermore, the cellular components used to generate these liver organoids combine a diverse group of starting cell sources, and for modeling a complex metabolic disease such as diabetes, this is not ideal.

Human adipose: There are emerging protocols for creating WAT from human pluripotent sources and primary tissue sources along with development of vascularized organoids and distinct ECM. The creation of a WAT engineered platform utilizing an isogenic iPSC source needs to be developed in conjunction with on-chip, validated assays of metabolic function such insulin-stimulated glucose uptake, adipokine secretion, lipid storage and oxidation capacities, and ultimately to demonstrate the plasticity of human WAT (such as "beiging") in response to cold or hormonal stimulation.

Incorporating immune components: Modeling how the immune system influences tissue function and pathophysiology using MPS-based platforms remains very challenging, but initial studies are showing some promise. Given the central role of inflammation in many chronic disease states, and the strong links between inflammation and metabolic dysfunction, a key goal of this initiative will be to provide systems that not only model normal organ physiology, but that also model interactions between the immune system and these MPS-based tissues under normal and pathophysiologic conditions.

The Tissues-on-Chips Consortium (The TC Consortium) is led and managed by NCATS and utilizes expertise (organ physiology, regulatory science, stem cells, bioengineering, etc.) from experts representing many institutes (including NIDDK), Centers and Offices at the NIH and the FDA. (http://www.ncats.nih.gov/research/reengineering/tissue-chip/tissue-chip.html ) This program supports an innovative approach to preclinical toxicity testing on human tissue: development of in vitro, three-dimensional organ systems from human cells on bioengineered platforms that mimic in vivo tissue architecture and physiological conditions in order to facilitate and accurately monitor key organ-level functions. The program has made substantial advances in developing multiple human tissue chips that can be physically integrated, and be used for drug/toxicity testing. The newly funded effort of the TC Consortium is to develop translatable in vitro models for preclinical efficacy studies, however, the pancreatic islet, liver, and WAT, as well as immune cell components are missing from this effort. This FOA supports the development of tissue chips from these "missing tissues". In keeping with the goals of the TC Consortium, once the iPSC-derived human islet, liver, and WAT chips are developed fully and tested for the ability of these systems to measure inflammation-driven pathophysiology, the next phase will be to generate an integrated micro system platform that can incorporate a bimodal, or multimodal biomimetic system and can be used to model aspects of a complex metabolic disease such as type 2 diabetes. The UH3 phase will therefore support studies to increase the complexity of the MPS-based models generated in the UG3 phase. It is expected that projects that progress to the UH3 phase will be focused on advancing 3 key aspects of MPS-MOD development: (1) linking multiple platforms together to measure crosstalk between metabolic tissues, (2) expanding the types and representation of immune cells in each of the organ-based systems, and (3) validating the utility of these systems to serve as experimental platforms for testing known diabetes drugs such as metformin, as well as, new and novel therapeutic strategies that preserve beta cell, adipocyte and hepatocyte functions and ameliorate diabetes.

Research Objectives and Scope

Applicants are invited to participate in a coordinated research effort focused on developing MPS to model human diabetes. Work will combine advances in stem cell biology, with the technological opportunities in tissue engineering that have led to the generation of microdevices that support aspects of functional, living organs. Applications should : 1) establish rigorous and reproducible protocols for the derivation of the pancreatic islet, liver, skeletal muscle, WAT, and/or immune system from a single isogenic iPSC source, 2) develop MPS platforms to support normal physiological function of the pancreatic islet, liver, skeletal muscle, and WAT, 3) develop on-chip functional assays that can offer quantitative, real-time monitoring, 3) integrate the human islet, liver, skeletal muscle and WAT tissue modules to establish models that feature the metabolic hallmarks of insulin resistance/type 2 diabetes, and 4) validate these models with known biomarkers and therapeutic agents of diabetes.

To be responsive to this FOA, all projects must develop at least two individual platforms for the human pancreatic islet, liver, skeletal muscle and/or WAT and must incorporate expertise needed to incorporate inflammatory components into the systems. Other relevant tissue chips for diabetes modeling may be added during the UH3 phase.

The MPS for the human pancreatic islet, liver, skeletal muscle and WAT are expected to individually re-create critical aspects of human physiology and provide measurable outputs for the representative system. Essential characteristics of the MPS should include all or some of the following features: 1) multicellular 3D architecture that represents characteristics of the tissues or organs; 2) models that closely mimic the normal physiology and can recapitulate tissue crosstalk between the pancreatic islet, liver, skeletal muscle and WAT; 3) reproducible and viable operation under physiological conditions maintained for up to 4 weeks in culture. Ideally, the platforms should provide spatial and temporal control of the cellular microenvironment, while enabling continuous monitoring (sensing), probing (direct in-cell measurements), and sampling (testing and continuous data collection and analysis) of the system. The primary focus of the UG3 phase will be to develop robust and reproducible protocols for generating an individual human iPSC-derived islet, liver, muscle, or WAT, that will accommodate the incorporation of tissue-resident immune populations and/or trafficking of immune cells within the tissue structure. The ultimate goal of the MPS-MOD program will be to produce multicellular platforms comprised of complex cell types that recapitulate key features of mature, adult-like function, whose components are derived from a single isogenic line, and to develop sensitive and reproducible assays for monitoring metabolic function and inflammatory-driven metabolic dysfunction. The applicant will identify quantifiable milestones (see below).

The UG3 phase:

• Robust protocols for deriving a human pancreatic islet, liver, skeletal muscle and WAT with adult metabolic function, and derivation of immune elements, all starting from a single isogenic iPSC line
• Development of non-invasive on-chip assays for monitoring metabolic function
• Development of single tissue/organ platforms that can be integrated in the UH3 phase
• Functional representation of a normal human MPS model
• Determine human diabetes relevance of the model by preliminary testing of key experimental features and outcomes essential to proceed to the UH3 phase of the study. This would include non-invasive endpoints that generate reproducible data under physiological conditions over a long culture period of up to 4 weeks.

The UH3 phase:

• Well-conceived plan to scale up to a fully integrated model during the 3 year Phase II period; integration of at least two or more human tissue chips with immune components in order to mimic bimodal or multi-component systems/axes relevant to diabetes
• Platform integration to study multiple organ pathology in disease and healthy models; and temporal representation of early to late phases of diabetes (pre-diabetes to T2D).
• Cross-validation of diabetes model end-points with clinical measures in humans
• Developing translatable pharmacodynamics for known and novel diabetes drugs and biomarkers
• Conducting pre-clinical efficacy testing of candidate therapeutics using innovative approaches, data acquisition and analyses
• Extensive characterization of clinical-pathological staging of the diabetes model with the corresponding stages of clinical disease using translatable biomarkers
• Developing strategies for rapid, open access dissemination of data and methodology, and for rapid distribution of disease models for their use in therapy development

UG3/UH3 Milestones

All projects will be milestone-driven with clear go/no-go criteria that are quantifiable and milestones must be included in the application. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a final set of approved UG3 milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the UG3 stage and progress towards interim milestones in the UH3 stage. Only UG3 projects that meet their milestones will have an opportunity to move to the UH3 phase. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage.

Examples of microsystems and potential diabetes modeling are listed below but are not limited to:

• Islet health and function, including glucose-sensitive insulin release and glucagon secretion
• Delivery of secreted products from islet to liver using microfluidics technology
• Liver responsiveness to insulin, incretins, adrenergic stimulation, glucagon, and other secreted factors.
• Effects of glycemic excursions, and nutrients on liver metabolism, glucose output, cholesterol, triglyceride synthesis, protein synthesis, energy metabolism and biliary excretions
• On-chip quantitative measures of lipids, metabolites, and proteins
• Introduction of GI hormones, nutrients and other substances to the liver chip using microfluidic technology to mimic a portal system.
• Re-creation of pathophysiology of fat tissues that occurs in disease states such as diabetes, obesity, and lipodystrophies.
• White adipose tissue, including visceral fat, that is associated with insulin resistance, low grade inflammation, dyslipidemia and cardiometabolic risk, and subcutaneous fat that has beneficial characteristics including storage of lipids, secretion of adipokines, positive metabolic effects such as lipid oxidation, energy utilization, enhanced insulin action and an anti-inflammatory role
• Inclusion of cell immune components (e.g. lymphocytes, macrophages, NK cells, neutrophils, or lymphoid tissue) and humoral components (e.g. cytokines/chemokines) to model inflammation
• Capacity to test biomarkers or candidate therapeutics
• Use of biomarkers or readouts to confirm that the diabetes model mimics human disease
• Application of genome manipulation strategies such as CRISPR/Cas9, Talen and Zinc-finger to introduce T2D risk variants

All methods, reagents, resources, biomaterials (including cell lines), protocols, data and models developed by MPS-MOD investigators are expected to be made available to the research community. Because the individual UG3/UH3 projects will be coordinated through MPS-MOD, the timeline and processes for sharing within MPS-MOD and with the community at-large will be established the MPS-MOD NIDDK Project Scientist or the MPS-MOD PD(s)/PI(s). All participants will be expected to adhere to these policies as a term of the award, consistent with achieving the goals of the program. Policy documents for MPS-MOD will be accessible on the NIDDK website.

Meetings of MPS-MOD

Program Directors(s)/Principal Investigators(s) of MPS-MOD must participate in an initial in-person MPS-MOD meeting soon after awards are made, in bi-annual in-person TC Consortium Meetings, as well as in quarterly MPS-MOD teleconference meetings. All participants will be obligated to abide by the policies adopted by the majority vote of the MPS-MOD steering committee. The PD/PI and up to two members of the project team must attend the initial in-person meeting and bi-annual in-person TC Consortium Meetings. All MPS-MOD teleconferences will be organized and administered by the NIDDK project team to coordinate the research projects to be conducted by the research grantees.

Additional Considerations

Cells: The use of primary human cells and tissues is encouraged, but the ultimate goal of this FOA is to develop robust and reproducible protocols for deriving tissues/organs from a single iPSC source.

Biomaterials: Native extracellular matrices are dynamic, complex microenvironments that can drive functional and biomechanical development. Applicants should consider the biological properties and potential downstream effects when choosing ECM materials. Biomaterials should be chosen to avoid confounding characteristics, e.g. the plastic polydimethylsiloxane (PDMS) binds hydrophobic drugs or reagents, which decreased the intended concentration, and can leach the endocrine disruptor cyclosilane into the media.

Collaborations: Collaborative interactions are a critical aspect of this FOA. The development of diabetes model systems will require extensive collaboration among tissue engineers, stem cell biologists, diabetes experts, and clinicians.

Applications that include the following types of studies will be considered non-responsive and will not be reviewed:

• Development of 3D tissues for transplantation
• Engineering of non-human tissue models
• Development of simple organoid models that do not go significantly beyond those currently available and in use
• Projects that develop only one individual platform for the human pancreatic islet, skeletal muscle and/or WAT
• Clinical trials

See Section VIII. Other Information for award authorities and regulations.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, incl 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 should be sent to:

John Connaughton, Ph.D.
Chief, Scientific Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7797
Email: NIDDKLetterofIntent@mail.nih.gov

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.

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

PDs/PIs are required to attend an initial kick-off meeting and bi-annual MPS-MOD Meetings in the Washington D.C. area. Funds to support travel of the PD(s)/PI(s) and up to two additional team members to attend the kick-off meeting and bi-annual meetings must be included in the budget.

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:

Specific Aims: Provide the overall goals for hypotheses for the entire project period and identify separate Specific Aims to be accomplished in the UG3 phase and in the UH3 phase.

Research Strategy: The applicant must:

• Provide separate sections that describe both the UG3 and UH3 phases
• Provide a description of the hypothesis to be tested in the UH3 phase of the study

Go/No-Go Transition Milestones for transition from the UG3 Phase to the UH3 Phase:

The applicant must:

• Include clearly identified Go/No-Go transition milestones for completion of the UG3 phase at the end of Year 2 and transition to the UH3 phase for 3 years of additional funding.
• A timeline (Gantt chart) including milestones is required for all studies. Yearly quantitative milestones are required in order to provide clear indicators of a project’s continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years.

Milestones and the timeline for each stage must be provided in a separate heading the end of the Approach section for each UG3 and UH3 component and include the following:

• Provide detailed quantitative criteria by which milestone achievement will be assessed.
• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

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

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

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

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

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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.

For this particular announcement, note the following:

The UG3/UH3 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. A UG3/UH3 grant application is not required to have extensive preliminary data, background material or preliminary information, but these may be included if available. Appropriate justification for the proposed work can also be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge of understanding. Reviewers will assign a single impact score for the entire application, which includes the UG3 and UH3 phases.

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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

Specific to this FOA: Is strong justification/rationale provided for transforming our understanding of normal human physiology and metabolic function, and tissue cross-talk of the pancreatic islet, liver, skeletal muscle and WAT? Is there a potential translational benefit derived for the development and use of the proposed insulin resistance/diabetes disease models? Is the MPS able to recapitulate normal biological indicators of metabolic function? Do the proposed disease models recapitulate clinically relevant models of tissue inflammation, insulin resistance and/or diabetes? Does the application focus on critical gaps to address important questions or obstacles in diabetes/metabolic disease? Will successful completion of the research aims promote an understanding of diabetes/metabolic disease pathogenesis and advance the future development of diagnostics and interventions?

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

Specific to this FOA: Is the Multi-PI leadership plan, if applicable, well-described, including plans for dispute resolution? Have project leadership and other key personnel demonstrated a track record of directing and conducting research activities related to creating and validating an MPS, creating and characterizing an iPSC-derived tissue, and have the expertise to create and validate clinically relevant on-chip assays, and models of insulin resistance/diabetes? Are the collaborations, in particular, from disease experts, well-documented, including provision of letters of support? Does the application provide a feasible strategy for collaboration among the scientific fields relevant to this FOA, i.e. disease experts, clinicians, tissue chip developers, stem cell biologists?

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?

Specific to this FOA: Are the overall goals of the application conducive to generating significant multidisciplinary investigations that respond to the overall objectives of the FOA? i.e. generating robust and reproducible protocols for generating iPSC derived tissues? Generating clinically relevant on-chip assays of function? Generating novel models for studies of inflammation, insulin resistance, and diabetes that will advance basic and translational science and/or future therapy development?

Does the project utilize the current advances of cutting edge technologies? Are the tissue chip platforms, combined with iPSC derivatives being proposed suitable to capture features of normal metabolic function and is the MPS appropriate for modeling disease?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? 

Specific to this FOA: Has the applicant included an adequate description and justification of the metabolic features that will be captured in the MPS and disease model? Are the technologies or experimental approaches state of the art or is there novel use of non-state of the art technology? Will the expected results lead to advances in technologies used in understanding the normal metabolic function of the human pancreatic islet, liver and WAT, as well as, the pathophysiology of diabetes? Are the proposed approaches, tools, and technologies scientifically justified for the particular MPS and disease model? Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible? Is the proposed transition plan to the UH3 phase complete and in a logical sequence to the elements of the phased UG3/UH3? Are the conceptual framework, testable hypothesis, design, bioengineered platform, microfluidics, biomechanics, iPSC source and differentiation protocols well-justified?

Milestones. Are appropriate, clearly-defined quantitative milestones provided for the UG3 and UH3 phases of the overall project? Are the UG3 and UH3 milestones feasible, well-developed and quantitative with regard to the specific aims within each phase? Is the overall timeline feasible for the UG3 and UH3 phases? Are the critical decision points (i.e. go/no go decision points) and timelines within the UG3 and UH3 phases appropriate? Are adequate criteria provided in the UG3 phase to assess milestone completion in order to make a decision to advance studies to the UH3 phase?

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?

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.

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.

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.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

Not Applicable

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.

Not Applicable

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).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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 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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.C. Office of management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardee 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 while, 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:

• Defining the details and goals for the project as a whole within the guidelines of this FOA.
• Determining experimental approaches, designing protocols, setting project milestones and conducting experiments
• Adhering to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity
• Submitting quarterly progress reports during the UG3 phase, in a format as agreed upon by the NIH Project team. Projects that are selected for continued support through the UH3 mechanism will submit progress reports also on a quarterly basis
• Accepting and implementing any other common guidelines and procedures developed for the NIH Project team. Projects that are selected for continued support through the UH3 mechanism will submit progress reports also on a quarterly basis
• Accepting and implementing any other common guidelines and procedures developed for the NIH Project Team
• Attending bi-annual workshops organized by NIH
• Managing all data acquired in a coherent database that will be available to government and private partners
• Coordinating, cooperating, and participating with NIH staff in the scientific, technical, and administrative management
• Identifying and maintaining infrastructure and collaborations needed to support the development of the proposed disease models(s)
• When needed, working with private partners to acquire and maintain reference compounds that industry partners will provide
• Working with NIH Program Officials and industry partners to establish context of use, standardizing and validating approaches
• Performing established standardization and validation milestones.
• Ensuring that all affiliated staff will maintain the confidentiality of the information developed by investigations, including, without limitation, informatic tools, protocols, data analysis, conclusions, etc. per policies approved by the consortium as well as any confidential information received by third party collaborators.
• Analyzing, publishing and/or publicly releasing and disseminating 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.
• Participating in a cooperative and interactive manner with NIH staff, other relevant consortia, including members of The TC Consortium and HIRN-CHIB, as well as one another.
• Sharing data, materials, informatics tools, methods, protocols, information and unique resources that are generated by the project as appropriate and in accordance with NIH policies in order to facilitate progress and consistent with achieving the goals of the MPS program.
• Working with the members of MPS for Modeling Diabetes Consortium and TC Consortium to establish agreements 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 with 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 as appropriate and consistent with achieving the goals of the program; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• Ensuring that for activities that involve academic and/or industry collaborations within and outside the MPS for Modeling Diabetes Consortium (MPS-MOD) and The TC Consortium, that there are appropriate research collaboration agreements (e.g. CRA, CDA, MTA etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement terms of award as well as any additional applicable NIH policies and procedures.
• Ensuring that the research is conducted in accordance with processes and goals as delineated in this Funding Opportunity Announcement.

Upon completion or termination of the project, ensuring all study materials, tools, databases and procedures developed from the project are broadly available (e.g. putting into the public domain) or made 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 within 90 days of the end of the study.

Publications

• The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the NIH project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments ca be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

• 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 Award (NoA).

Specifically, the NIDDK Project Scientist will be substantially involved in this project as follows:

• Coordinate and facilitate the activities of the program, attend and participate in all meetings of the MPS for Modeling Diabetes consortium
• Work with NIDDK Program Director and other NIDDK MPS-MOD project team members, to review the scientific progress and administrative accomplishments of the awardees, and review the project for compliance with operating policies and procedures, including meeting milestones. Based on this review, the Program Officer may recommend to the NIH to continue funding, or to withhold or restrict support for lack of progress or failure to adhere to NIH policies. Review of progress may include regular communications between the Principal Investigator and NIH staff, periodic site visits for discussion with research teams, fiscal review, and other relevant matters.
• Prepare up-to-date summaries of program accomplishments based on manuscripts provided by the awardee within two weeks of acceptance for publication
• Participate (with the other Tissue Chip trans-NIH Team members and NIDDK MPS-MOD project team staff) in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols, project milestones or approaches as warranted
• Serve as a liaison between the awardee, the Advisory Councils for those Institutes that plan to administer elements of the MPS-MOD and the larger scientific community
• Coordinate the efforts of the awardee with others engaged in microphysiological system research, including the other awardees under this FOA, and those awardees involved in related NIH programs
• Attend all NIDDK project team meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action
• Periodically report progress to Directors and NIH institutes involved in the MPS-MOD consortium
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the award institutions who are to serve as External Scientific Panel members, as needed
• Provide input into the design of research activities and play a key role in coordinating research efforts
• Monitor milestone progress and help identify recourses if needed
• Endure the awarded project(s) adhere to cooperative agreement data-sharing and other resource-sharing policies
• Facilitate collaborations with and access to other NIH-supported research resources and services
• 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 Project Scientist.
• The NIH Project Scientist serves as a resource with respect to other ongoing NIH activities that may be relevant to MPS-MOD studies to facilitate compatibility and avoid unnecessary duplication of effort.
• Provide advice on project management and technical performance
• The NIH reserves the right to curtail or phase out the award in the event of (1) a substantial shortfall in accomplishing the management goals and responsibilities as stated in the reviewed application, (2)failure to meet procedures and milestones, and/or (3)substantive changes in the management of award(s) that are not in keeping with the objectives of the FOA
• The NIH will enlist additional scientific consultants as necessary from within the NIH, other government agencies, and from other industry partners whose function will be to assist the Program Director 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.

Communication Plan

• Participating in regular (quarterly) conference calls with the Project Scientist and Program Officer
• Coordinating efforts with other awardees, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the consortium
• Participating and presenting findings at the semi-annual workshops and/or teleconferences convened by the NIH
• Coordinating or jointly publishing findings in a timely manner, and as to have the broadest impact
• Making new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIDDK program project team and other mechanisms

Areas of Joint Responsibility include:

• Collectively, awardee(s) and the Project Scientist will determine criteria and processes for quality control of information and data to be posted for the research community, consistent with NIH policies and achieving the goals of the program as described in this Funding Opportunity Announcement.
• Participate in recurring quarterly meetings to discuss progress, obstacles and any other consortium related issues and/or activities

In addition to quarterly MPS-MOD teleconferences, there will be an initial face-to-face meeting of MPS-MOD, and a minimum of 2 MPS-MOD meetings at the NIH annually. Awardee(s), the MPS-MOD Project Scientist and the MPS-MOD Program Official are expected to attend these meetings. Both of these biannual meetings could be combined with The TC Consortium meetings. If a single award is made, then MPS-MOD will be governed by the PI and the NIH Project Scientist.

Steering Committee

If multiple UG3s are funded, then MPS-MOD agree to the governance of the study through a Steering Committee.

• On an annual basis, NIDDK staff will appoint a Steering Committee chair who will be in charge of facilitating 2 MPS-MOD teleconferences.
• In collaboration with the NIH Project Scientist, the Chairperson is responsible for coordinating the Steering Committee activities, for preparing meeting agendas and for chairing meetings.
• 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 Principal investigators/Program Directors for each UG3/UH3, or by UG3/UH3 representatives chosen by the Principal Investigators/Program Directors in the case of Multi-PI grants, and the NIH project Scientist. Only the UG3/UH3 PI/PD or multi-PI UG3/UH3 representative 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 MPS-MOD steering committee will meet at least twice a year by teleconference.
• 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. 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 UG3/UH3 grant(s) if it is considered to be 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 much serve on MPS-MOD subcommittees as needed. Subcommittees will report at Steering Committee Meetings and/or lead discussions at the TC Consortium biannual meetings.

Expert Scientific Panel (ESP)

An independent panel of 2-5 External Experts will be appointed by the NIDDK and meet by teleconference with the MPS-MOD Project Scientist and the MPS-MOD Project Officer at least once a year. The MPS-MOD will be updated on progress and give feedback to the MPS-MOD PI/PDs, Steering Committee and NIH on adjustments and future directions for the MPS-MOD research project(s).

Intellectual Property

The successful development of disease models using microphysiological systems platforms and the integration of these microsystems within a common platform may require either substantial investment and support by private sector industries, and/or may involve collaborations with other organizations such as academic, other governmental agencies, and/or non-profit research institutions not directly involved in the NIH-funded MPS for Modeling Diabetes Program. NIH recognized that intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, all awardees shall understand and acknowledge the following:

• The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the award to perform the project.
• The awardee is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C Sect. 202 (Bayh-Dole Act).

Data

Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution 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 D, and HHS regulations at 45 CFR Part 16.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Sheryl M. Sato, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8811
Email: smsato@mail.nih.gov

Danilo Tagle, Ph.D
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064 
Email: Danilo.Tagle@nih.gov

Elena Sanovich, Ph.D. 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8886
Email: sanoviche@mail.nih.gov

Craig Bagdon
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-2115
Email: bagdonc@mail.nih.gov

Ki-Cha Flash
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0846
Email: flashk@mail.nih.gov

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 Part 75.