Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

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

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Human cell-based assays (e.g., using induced pluripotent stem cells) hold promise for identifying molecular, cellular and circuit defects, identifying novel targets and developing new therapeutics for patients with complex brain and other nervous system disorders. However, the methods to generate and analyze relevant cells and circuits must be made robust, replicable and predictive for normal nervous system function as well as pathophysiology. Cells grown in monolayer culture remain a mainstay for many assays, including high-throughput screening, but a drawback of these reductionist assays is that they cannot resolve many developmental and aging trajectories, anatomical features and circuit activity representative of in vivo nervous system function.

As an alternative, there are increased efforts to generate assays with more physiologically-relevant organization. For example, microphysiological systems (MPS) are structured three-dimensional (3D) culture assays. One version is organoid or spheroid culture, which is a non-adherent suspension culture that relies on the self-organizing properties of stem cells in the absence of a substrate. Another type of MPS is the tissue chip, which is a multicellular structure that represents minimal units of organ function and is embedded in a non-living microfluidic platform; this allows both efficient exposure to test compounds and efficient physiological readout. A third way to evaluate integrative cell function is by introducing human cells into another live species (known as chimeras or xenografts). While these assays currently reproduce some important features of in vivo prenatal development, a major unresolved technical hurdle is the application of human cell-based assays to evaluate circuit maturation, connectivity and aging, including its relationship to specific circuits involved in disease states. Addressing this complex technical challenge requires the collaboration of experts from diverse fields, including developmental and stem cell biology, circuit and systems level neuroscience, materials science, engineering and bioethics.

Research Objectives

The purpose of this Notice of Funding Opportunity (NOFO) is to stimulate basic technology-focused research to develop next-generation human cell-derived MPS and related assays with improved fidelity to complex human brain, spinal cord, and/or sensory end organ circuit physiology, which will ultimately facilitate analysis of higher order functional deficits relevant to complex nervous system diseases. This NOFO is distinct from others that focus on optimization and scalability of assays for compound screening, although projects could, in principle, have utility for late stage evaluation of drug efficacy and toxicity. These models will have a multi-lineage, complex architecture representing the normal characteristics and functions of the relevant nervous system structure (e.g., sensory input systems, brain or spinal integrative systems, motor output systems) and will substantially exceed the state of the art in cellular maturation and integration, allowing reproducible measurement of human-relevant circuit-level activity under physiological conditions over a long period.

This NOFO encourages innovative approaches that are first-in-class, those that propose to substantially exceed the state of the art in tissue organization and function. These can be high risk, high impact designs. Additionally, this NOFO encourages approaches that aim to improve robustness and reproducibility of physiologically relevant circuit or supportive systems-level measures.

All applications should define the current state of technology as a benchmark against which the new assay system(s) will be developed and measured. Example approaches include, but are not limited to:

• Utilization of novel materials, substrates or synthesis technologies (e.g., 3D printing, bioreactors, microfluidic platforms) to promote anatomically and physiologically relevant tissue organization and/or maturation.
• Integration of defined cell types consistent with relevant nervous system anatomy (e.g., excitatory, inhibitory & modulatory neurons, astrocytes, oligodendrocytes, microglia, pericytes, endothelial cells) into functional units (assembloids) that may include multipartite synapses, vascularization-perfusion, blood-brain barrier, glymphatic system and/or cerebrospinal fluid flow.
• Novel strategies to faithfully reproduce relevant regional cellular organization (e.g., dorsoventral, rostrocaudal, laminar, columnar or nuclei structure), with both short- and long-range anatomical connectivity (e.g., local inhibitory-excitatory and/or modulatory connections, projections to distant lamina or nuclei).
• Novel strategies to promote maturation of metabolism, signaling, synaptic activity, and connectivity in the cell-based assay.
• Development of human cell-based assays with complex functional features relevant to complex nervous system disorders and diseases (e.g., intrinsic and/or dynamical network properties of cell assemblies such as neural oscillatory activity, activity-dependent plasticity).
• Inclusion of conditional or intersectional strategies that allow temporally and/or spatially cell-selective monitoring or manipulation of gene expression/function or of live cell activity and function.
• Inclusion of innovative approaches to distinguish or deconvolute heterogeneous cell phenotypes in these assays (e.g., multi-parameter single cell analysis), including those that are minimally perturbing.
• Evaluation of how data obtained from the proposed assay compares with human anatomical, histological or systems-level data, or data from other physiologically relevant paradigms, to facilitate assay validation. Investigators are encouraged to explore data and tools being developed under the NIH BRAIN Initiative, BrainSpan, PsychENCODE and the PsychENCODE Human Brain Development Atlas, Human Connectome Project, AMP-AD, or related efforts which, if utilized, could further the authentication of human brain cell-derived assays.

Interests of Specific Institutes/Centers

The scientific interests of participating Institutes and Centers (I/Cs) are summarized below. Applicants are encouraged to contact the Scientific/Research contact of the intended I/C to ensure that the aims of the proposed project are consistent with the I/C mission.

National Institute of Mental Health (NIMH)

NIMH is interested in all example approaches from the Research Objectives that facilitate Next-Generation MPS representing the cellular and circuit substrates of cognitive, social and affective domains of brain function. Examples from the Research Objectives can include, but are not limited to, generating correctly-specified and anatomically organized brain regions that subserve these domains of function, integration of vascularization-perfusion, blood-brain barrier or other systems-level support features into these structures; optimizing local excitatory-inhibitory-modulatory feedback circuits representing cortex or subcortical regions, longer distance cortico-cortical, cortico-striatal, thalamo-cortical and cortico-limbic connections, the emergent systems-level features (e.g., oscillations) that arise from such circuit activity and the effect of changing input on circuit behavior (e.g., transfer functions). Applications should be primarily focused on MPS technology development and basic biology, although the domains of function should be relevant to those potentially dysregulated in mental illnesses, including autism spectrum disorders, mood and anxiety disorders (e.g., bipolar disorder), attention deficit and obsessive-compulsive disorders, and/or schizophrenia. While applications can include independent variables for validating the utility of the MPS for studying a relevant cellular/synaptic/circuit activity or domain of function (e.g., comparison of isogenic lines with and without engineered gene variants), the central focus should be on developing or improving MPS technology and not studying disease biology per se. Applications focusing on developing or utilizing cell-based assays to study mechanisms of mental illnesses can respond to PAR-24-024 and PAR-24-025.

National Eye Institute (NEI)

NEI is interested in research proposing to develop Next Generation MPS that more closely recapitulates the cornea, lens, retina, RPE, and/or elements of the central visual pathway. Projects suitable for this announcement include, but are not limited to 1) the development of natural and/or synthetic substrates/scaffolds that promote the growth and differentiation of physiologically relevant tissue; 2) the development of microfluidic devices (eye-on-chip) derived from stem cells that model physiological functions of the visual system; 3) the development of 3D tissue platforms that model microenvironments or niches of the visual system; 4) the development of MPS with complex functional features such as circuit structure, function, and connectivity as it relates to the visual system. Demonstration of how MPS systems are improvements over animal models or other 2D in vitro systems is also desired. While it is necessary to evaluate the basic biology of the 3D tissue, the primary focus should be on the improvement of the MPS technology and to more faithfully recapitulate development and not on basic disease mechanisms, transplantation procedures, personalized gene therapy approaches, and/or therapeutic and toxicity screens.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

NIAAA supports the generation of MPS that recapitulate nervous system tissues and brain structures throughout the lifespan. NIAAA is seeking applications for new technologies that can assess the effects of alcohol on 1) cellular physiology, 2) neural circuit formation, maintenance and plasticity, and 3) interactions of multiple cell types (neurons, glia, vasculature, and immune cells) during critical developmental stages. The institute is interested in platforms to test underlying genetic and epigenetic consequences of short and long-term alcohol exposure and the actions of drugs and potential therapeutic compounds for prevention of alcohol use disorder or other consequences of alcohol exposure. The MPS may provide a platform for the generation and testing of predictive models of molecular, cellular and/or neural circuit responses to acute and chronic alcohol exposure (use) and reveal candidates for risk of and resiliency for fetal alcohol spectrum and alcohol use disorders.

National Institute on Deafness and Other Communication Disorders (NIDCD)

The National Institute on Deafness and Other Communication Disorders (NIDCD) has a continued interest and effort to support new opportunities that could provide faster, more efficient biological platforms to assess physiological function, disease models, and transplantation potential in the NIDCD mission areas of hearing, balance, taste, smell, voice, speech and language. The institute is interested in a broad variety of approaches and technology/methodology development. Some examples, but not limited to, would be technical development of microarchitecture reagents including appropriate buffers, media, polymers and synthetics to generate improved 3D platforms and microenvironments to facilitate cellular attachment, proliferation, in areas of differentiation or regeneration of taste buds, hearing/balance sensory epithelium, or vocal folds; experimental improvements of drug assessment studies, high throughput replication and comparative analyses of laryngeal, chemosensory and auditory/vestibular function (e.g., ototoxicity, noise or drug trauma, and age-related sensory loss); experimental improvements to implantable chip or scaffold-derived tissues and cells, such as for vocal fold replacement or inner ear transplantation studies; use of improved stem cell technology for the derivation of multi-cellular chip organoids replicating normal and/or disordered tissue physiology; use of gene and protein manipulation technologies to enhance the imaging and/or assessment of the created chip microsystem (e.g., cellular identities, function, and interactions, neuronal innervation, or molecule activity).

National Institute on Aging (NIA)

The National Institute on Aging (NIA) is interested in the development of next-generation MPS that more closely recapitulate the aging brain and diseases of brain aging. While applications should be primarily focused on MPS technology development, the circuits and brain regions of interest should be relevant to either those declining during brain aging or those resilient to the effects of brain aging. NIA is interested in all examples of approaches listed under the Research Objectives that would promote understanding of the aging brain and diseases of brain aging, particularly Alzheimer’s disease. Examples of projects that would be appropriate for this announcement include, but are not limited to: 1) using new technologies to develop three-dimensional human cell-based assays that better recapitulate brain aging, including the integration of defined brain cell types into functional units and mechanisms to study cell-cell interactions during aging and Alzheimer’s disease; 2) promoting maturation of metabolism, neuroimmune interactions, signaling, synaptic activity, and connectivity in the human cell-based assay to recapitulate the aging brain; and 3) developing human cell-based assays with complex functional features relevant to nervous system disorders of aging, including cell-selective manipulation of gene expression or cell function to model normal and disordered brain aging, such as occurs in Alzheimer’s disease. Although applications can include disease-relevant perturbations for model validation and testing assay utility, the focus should be on developing or improving MPS technology. Applications proposing to use existing cell-based assays to study aging-related and Alzheimer’s disease mechanisms should respond to NOT-AG-21-052 via PAR-22-093 (R01) or PAR-22-094 (R21) or any reissues of these announcements.

Non-Responsive Topics

Applications addressing the following topics are not responsive to this NOFO:

• A central focus on scaling assays or adapting for use in compound screening.
• Strategies directed toward cell therapy or regenerative medicine.
• Developing organoid or other MPS assays from exclusively non-human tissues.
• Assays that aim to recapitulate 3-germ-layer gastrula-like structures (e.g., gastruloids).
• Assays based on pre-gastrulation human-nonhuman chimeric manipulation, or those potentially involving human contributions to the germline.
• Utilization of existing technologies that do not significantly advance the state of the art to address disease-relevant questions.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local 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).

Federal Governments

• 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 Organizations)

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

Note that the application should include expert collaborators appropriate for the particular needs of the assay being optimized, e.g., developmental or aging neurobiology, stem cell biology, circuit and systems level neuroscience, materials science, engineering and/or bioethics.

R&R or Modular Budget

All instructions in the How to Apply- Application Guide must be followed.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

Research Strategy: The primary focus of applications responding to this announcement is developing technologies involving human cell-based engineering of MPS or related assays, directed as described in the Research Objectives toward faithfully representing salient features of in vivo brain, spinal, and/or sensory end organ circuit physiology, that may include systems-level features that support circuit function (e.g., myelination, vascularization-perfusion, blood-brain barrier, glymphatic system, cerebrospinal fluid flow). As a result, applications should focus on technical improvements to and capabilities of these cell-based assays relative to current state of the art. While genetic or environmental perturbations relevant to disease states can be incorporated into the research design as a means of validating the specific utility of the assay, these are neither required nor expected.

The research strategy should:

• Exploit novel tools or technologies, including those from other disciplines, to improve the sophistication, robustness or reproducibility of nervous system assay. Alternatively, it should bring a unique conceptualization of analytic approaches being applied to the assay.
• Address an intransigent barrier to (or propose to substantially exceed the state of the art in) cellular maturation and integration within the assay. Alternatively, the plan should aim to improve robustness and reproducibility of physiologically relevant circuit or supportive systems-level measures.
• Address the goal of improving assay’s fidelity to salient features of in vivo neural circuit structure and function and/or systems-level features that support circuit function.

• Define the current state of the human cell-based assay technology as a benchmark against which the new assay(s) will be developed and measured.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide.

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• Additionally, applicants should describe how protocols for generating and validating the assay, with sufficient detail to facilitate replication, will be disseminated to the research community. Applicants are expected to register resources supported by this NOFO in the Neuroscience Information Framework (https://scicrunch.org/) and use Research Resource Identifiers (RRID) in any publication supported by this NOFO.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this NOFO are expected to share those data via the National Institute of Mental Health Data Archive (NDA). Established by the NIH, NDA is a secure informatics platform for scientific collaboration and data sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to the NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant and b) a budget strategy that will cover the costs of data submission. The NDA website provides two tools to help investigators develop appropriate strategies: 1) the NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page. Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information). Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied. NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- 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 How to Apply- Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply- Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply 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 NIA, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports investigation of novel scientific ideas or new model systems, tools, or technologies that have the potential for significant impact on biomedical or biobehavioral research. An R21 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21 applications; however, they may be included if available.

As the NOFO encourages innovative approaches to major methodological challenges, the level of risk is generally expected to be higher than for conventional R21 applications. The primary focus of applications responding to this announcement is developing technologies involving human cell-based engineering of MPS or related assays, directed as described in the Research Objectives toward faithfully representing salient features of in vivo brain, spinal, and/or sensory end organ circuit physiology, that may include systems-level features that support circuit function (e.g., myelination, vascularization-perfusion, blood-brain barrier, glymphatic system, cerebrospinal fluid flow). As a result, reviewers should primarily assess merit based on the technical improvements to and capabilities of these cell-based assays relative to current state of the art. While genetic or environmental perturbations relevant to disease states can be incorporated into the research design as a means of validating the specific utility of assays, these are neither required nor expected.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

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

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the Center for Scientific Review, 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 will receive a written critique.

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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH 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 NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and 
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

Not Applicable

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

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

Amanda DiBattista, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: [email protected]

Nancy Freeman
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: (301) 402-3458
E-mail: [email protected]

Lisa Neuhold
NEI - NATIONAL EYE INSTITUTE
Phone: 301-443-5401
E-mail: [email protected]

David M. Panchision, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: [email protected]

Elizabeth Powell, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-443-0786
E-mail: [email protected]

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Robin Laney
National Institute on Aging (NIA)
Telephone: 301-496-1473
Email: [email protected]

Samantha J Tempchin
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: (301) 435-1404
E-mail: [email protected]

Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: [email protected]

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: (301) 443-4704
E-mail: [email protected]

Section VIII. Other Information

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

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 2 CFR Part 200.