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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Goal 1 of the National Plan to Address Alzheimer’s Disease is to prevent and effectively treat Alzheimer's disease (AD) and Alzheimer’s disease-related dementias (ADRD) by 2025. ADRD are defined as Vascular Contributions to Cognitive Impairment and Dementia (VCID), Frontotemporal Dementia (FTD), Lewy Body Dementias (LBD), and Multiple Etiology Dementias (MED). Starting in 2012, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held research summits to assess the needs and set AD/ADRD research implementation milestones. The NINDS ADRD Summit 2022 resulted in ADRD research priorities for advancing the state-of-the-science toward meeting Goal 1 of the National Plan. This NOFO responds directly to the VCID research milestones established by the ADRD Summit 2022. 

While the significance of VCID in many dementia diagnoses is now recognized, fundamental knowledge is needed to optimally leverage that significance toward better lifetime outcomes in populations and in individuals including in the context of other AD/ADRD-relevant co-morbidities. The purpose of this NOFO and CWOW program is to support research that will, in parallel in human-based and model-based studies, increase fundamental understanding of small vessel VCID diseases and their impact on the structure and function of the neurovascular unit that over time, alone or with co-morbidities, results in cognitive impairment and dementia outcomes. By leveraging advances in single cell analytic techniques (see non-responsive criteria), imaging, and other approaches this program will provide a forward-looking framework for supporting discoveries that will be foundational for next critical steps in leveraging small vessel cerebrovascular disease health and mechanisms for lessening the future burden of dementia.

Specifically, this NOFO will solicit applications focusing on fundamental mechanistic understanding of arteriolosclerosis, CAA, and atherosclerosis (direct impact or downstream effects on small vessels), as well as how these disorders respond to potential and approved therapeutics against dementia. Research will use multi-faceted approaches to understand these small vessel disorders both cross-sectionally and over time (prodromal and after phenotypic disease first develops), as well as their relationship to VCID phenotypic and clinical outcomes, via collaborative approaches including but not limited to the following: single-cell analyses (e.g., genetic, protein, other molecular and physiological analyses); integration with the neurovascular unit; impact on synapse, circuit and network function. De-identified human tissues and clinical data will be used in this research, with parallel cross-referencing studies in model-based systems.

This CWOW program will provide the opportunity for projects to move forward individually, and at the same time is designed to facilitate synergy among the funded projects via required virtual and annual in person meetings. Teams will engage in pre-publication sharing of data, methods, and results during these meetings. In addition to analyses performed directly under each award, to facilitate future opportunity for long term goals, rigor, and impact, including synergy with other major NIH programs such as the BRAIN initiative, awardees will be asked to share human omics sequencing libraries that are used with an NIH-funded resource. The overarching objective of this program is to generate, via a collaborative CWOW framework, foundational knowledge in the emerging field of VCID that is needed for future development of interventions and better prevention and outcomes for human ADRD.

Applicants are encouraged to consider including investigators with a broad range of expertise including (but not limited to) the following: clinical and pathological expertise in arteriolosclerosis, CAA, and atherosclerosis; VCID; reverse and forward translation; AD/ADRD models and manipulations including loss of function and gain of function; rigor in experimental design; single-cell analyses (could also include other ‘omics approaches); neurovascular unit; synapses, neural circuits, and network function; biostatistical analyses needed to ensure experimental planning with appropriate statistical design and power analyses; data science, including big data, harmonization, interoperability and sharing.

Applications Not Responsive to this NOFO

• Applications that are not primarily focused on small vessel VCID.
• Applications that do not have a significant focus on at least one (or more) of: cerebral small vessel disease including arteriolosclerosis, CAA, and atherosclerosis (direct impact or downstream effects on small vessels).
• Applications that do not utilize de-identified human tissues and de-identified clinical data together with parallel cross-referencing studies in model-based systems, including at least one in vivo model of small vessel VCID including at least one of arteriolosclerosis, CAA, or atherosclerosis (direct impact or downstream effects on small vessels).
• Applications that do not use human autopsy tissue for single cell analyses.
• Applications that do not include a component designed to increase understanding of interactions between small vessel VCID and at least one other AD/ADRD relevant pathology (for example, but not limited to, the following proteinopathies: beta-amyloid, tau, TDP-43, alpha-synuclein).
• Applications that do not indicate, beyond standard NIH requirements for sharing, a commitment to NOFO-specific sharing requirements, namely: pre-publication sharing of data, methods, and results at CWOW meetings; sharing with an NIH-funded resource of any human omics sequencing libraries used under this funding mechanism.
• Applications that include one or more NIH-defined clinical trials.
• Human subjects research is not responsive, unless the human subjects research meets the E4 exemption (i.e. entirely de-identified human samples, cells and clinical data). For help determining if your research is considered human subjects research, please see here: https://grants.nih.gov/grants/policy/hs/private-information-biospecimens-flowchart.pdf. For help determining if your human subjects research meets the E4 exemption, please see here: https://grants.nih.gov/sites/default/files/exemption_infographic_v8_508c_1-15-2020.pdf.

Applications not responsive to this NOFO will not be reviewed.

Rigor and Transparency

NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (https://www.ninds.nih.gov/Funding/grant_policy). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

Applicants can consider leveraging existing research resources including from but not limited advocacy groups, private research foundations, academic institutions, NIH, and other government agencies. Such resources may include clinical biospecimen samples from the NINDS Human Biospecimen and Data Repository (BioSEND; https://biosend.org/), NINDS Human Cell and Data Repository (https://stemcells.nindsgenetics.org/), NeuroBioBank (https://neurobiobank.nih.gov/), or other existing biospecimen, imaging and data repositories.

Applicants are encouraged to contact the NINDS Program point of contact for this NOFO with any questions prior to application.

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 Government

• 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• 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 registration; 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.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Roderick A. Corriveau
Email: roderick.corriveau@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 NOFO.

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.

Other Attachments:

Applicants are required to include the following items in the Other Project Information section of the application: (i) A Cross-CWOW Coordinating Team (CCCT) Management Plan; and (ii) An Intellectual Property Strategy. These items must be uploaded as separate attachments in pdf format with filenames that correspond to the individual items (e.g. CCCT Management Plan.pdf, Intellectual Property Strategy.pdf). Applications lacking these required items will be deemed incomplete and will not be reviewed.

(i) Cross-CWOW Coordinating Team (CCCT) Management Plan:

Each application to this NOFO must have a proposed CCCT Management Plan. The CCCT Management Plan must not exceed three pages. Applications that exceed this limit will be withdrawn. The CCCT Management plan must include a named Lead with appropriate skills and experience who will be the CCCT point of contact. One CCCT will be selected among the funded applications. This CCCT will facilitate CWOW-wide functions indicated below to enable and drive both logistic and scientific synergy. Specifically, the CCCT will be responsible for the following, which will be included in the Notice of Award (NOA):

• Development and of execution of CWOW-wide confidentiality agreements with respect to the sharing of pre-publication data from, and protocols for, implementation of the specific aims of awards under this NOFO. These agreements will include commitment to strict confidentiality of all materials and discussions and information shared at meetings convened by the CCCT. The CCCT is to ensure execution of these agreements with all CWOW awardees under this NOFO within 5 months of NOAs being issued.
• Establishing and maintaining a secure platform for intra-CWOW sharing of protocols and data. The platform is not intended to be a repository of data per se, but rather the platform will offer a secure avenue for sharing data, protocols, and other information under the CWOW-wide confidentiality agreements.
• Organization of CWOW Meetings:

(1) In Person Meetings. The CCCT is to hold an in-person Kickoff Meeting within six months of NOA, with annual in-person meetings thereafter during the award period. This includes all logistics, with input from other CWOW awardees and the NINDS such as but not limited to: selection of date and location, development of the agenda, reserving and funding meeting room venue with appropriate audiovisual (in person meetings will not be recorded and will not have a virtual option), reserving accommodation venue (travel will be budgeted for by individual CWOW applications, not by the CCCT, except for as indicated in iv and v below), printed materials for meeting, etc. In brief, planning, organizing, and implementing in-person meetings with the following attendees:

(i) Up to 25 CWOW investigators (up to 5 per award, with travel budgeted for these 5 by each separate CWOW application). Contact PI attendance is required.

(ii) Up to 3 NINDS staff (not to be budgeted for by CCCT).

(iii) The CCCT is to budget travel support for up to 10 trainees with prioritization of individuals from diverse backgrounds and/or early career individuals. Trainee attendees supported by the CCCT are to be nominated by CCCT on behalf of the CWOW contact PIs, and must be concurred upon by the NINDS Program Officer (PO).

(iv) The CCCT is to budget travel for up to 6 additional outside guest scientists to be nominated by CCCT on behalf of CWOW contact PIs who would also sign confidentiality agreements as a condition of attending.

(2) Virtual Meetings: Planning, organizing, and implementing, six months after the kickoff meeting, and annually thereafter a required virtual meeting for contact PIs (who are required to attend) and other attendees, as outlined above.

In addition to naming a CCCT Management Plan Lead, the CCCT Management Plan is to outline specific strategies and approaches to perform the CCCT functions outlined above. The CCCT Management Plan is also to describe why the proposed plan strategy and staff are suited for the overall CCCT goal of creating and maximizing opportunities for scientific synergy across the CWOW, including with specific proposed approaches – not only during the required meetings, but also on a continuous and iterative basis.

(ii) Intellectual Property Strategy:

Applications must include an Intellectual property (IP) strategy that is no more than two pages in length. Applications that exceed this limit will be withdrawn.  Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, as applicable.

The goal of this program initiative is to advance research towards the development interventions that will benefit the public. Accordingly, applicants should describe relevant copyright and IP landscape for their application, if applicable. This should include any known constraints that could impede development (e.g., copyright considerations, certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies/paradigms/drugs that are under copyright, patent and/or are on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If the applicant proposes using a device or technology or drug whose IP or copyright is not owned by the applicant's institution, the applicant should address any questions that may constrain or impede the ability to operate and move the technology forward consistent with achieving the goals of the program. Applicants should include a letter (see Letters of Support) from the entity that owns the IP indicating whether the entity will provide the device or technology, if there are any limits on the studies that can be performed with that device or technology, and agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.

If copyright or patents pertinent to the paradigms developed under this application have been filed, the applicants should indicate the details such as filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable. Applicants should also discuss future copyright or IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application both within and outside the CWOW. Applicants must clarify how IP will be shared or otherwise be managed with other CWOW members. All existing and planned IP and/or copyright that impacts or may impact sharing of information and reagents in the CWOW must be disclosed and discussed in the application.

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

R&R or Modular Budget

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

R&R Subaward 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:

Research Strategy

All Research Strategy instructions must be followed and addressed in the application.

Describe how the proposed research, with a significant focus on one or more of cerebral small vessel diseases including arteriolosclerosis, CAA, and atherosclerosis (direct impact or downstream effects on small vessels) will use multi-faceted approaches to:

• Understand brain small vessel disorders, both cross-sectionally and over time (prodromal and after phenotypic cognitive decline first develops), as well as their relationship to VCID phenotypic and clinical outcomes
• Advance foundational molecular mechanistic understanding of VCID by using de-identified human tissue and clinical data in parallel with, and mechanistically cross-referencing with, studies in model-based systems including, ideally, both loss of function and gain of function studies.
• Increase fundamental understanding of function and dysfunction of the neurovascular unit, synapses, circuits, and networks in the context of VCID and AD/ADRD overall, including in mixed dementias.
• Contribute to foundational knowledge that will proactively promote development of future VCID interventions including for prevention and better clinical outcomes.

Indicate how the proposed research includes one or more components designed to increase understanding of interactions between small vessel VCID and at least one other AD/ADRD relevant pathology (for example, but not limited to, the following proteinopathies: beta-amyloid, tau, TDP-43, alpha-synuclein).

CWOW Investigators:

Describe how the investigators have a broad range of expertise including (but not limited to) the following: clinical and pathological expertise in arteriolosclerosis, CAA, and atherosclerosis; VCID; reverse and forward translation; AD/ADRD models and manipulations including loss of function and gain of function; rigor in experimental design; single-cell analyses; neurovascular unit; synapses, neural circuits, and network function; biostatistical analyses needed to ensure experimental planning with appropriate statistical design and power analyses; data science, including big data, harmonization, interoperability and sharing; all other expertise needed to effectively and successfully carry out the proposed research.

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. 

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) 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.
• In the Data Management and Sharing Plan, applications must indicate, beyond standard NIH requirements for sharing, a written commitment to sharing, within the CWOW, of pre-publication ideas, data, methods, and results to effectively reach the goal of this collaborative program that will also be specified in the terms of the NOA.
• Sharing of DNA Sequencing Libraries: applications that propose to use any DNA sequencing approaches for the analyses of human brain tissues (including but not limited to single cell or single nuc omics) must, in addition to sequencing and analyses proposed as part of the CWOW, describe a plan and budget for producing enough of each library such that the libraries can be, within 3 months of request by the NINDS, safely shipped to an NINDS designated sequencing facility for independent sequencing and data sharing. Commitment to this requirement must be stated in the Resource Sharing Plan.

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

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 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.

Human subjects research is not responsive, unless the human subjects research meets the E4 exemption (i.e. entirely deidentified human samples, cells and clinical data). Use of de-identified human tissue and de-identified clinical data is responsive. For help determining if your research is considered human subjects research, please see here: https://grants.nih.gov/grants/policy/hs/private-information-biospecimens-flowchart.pdf. For help determining if your human subjects research meets the E4 exemption, please see here: https://grants.nih.gov/sites/default/files/exemption_infographic_v8_508c_1-15-2020.pdf.
 

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 SF424 (R&R) Application Guide must be followed.

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

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

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

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 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 SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

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 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 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

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:

Overall Impact

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

Scored Review Criteria

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

Significance

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

Investigator(s)

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

Specific to this NOFO:

To what extent do the investigators have a broad range of expertise including (but not limited to) the following: clinical and pathological expertise in arteriolosclerosis, CAA, and atherosclerosis; VCID; reverse and forward translation; AD/ADRD models and manipulations including loss of function and gain of function; rigor in experimental design; single-cell analyses; neurovascular unit; synapses, neural circuits, and network function; biostatistical analyses needed to ensure experimental planning with appropriate statistical design and power analyses; data science, including big data, harmonization, interoperability and sharing; all other expertise needed to effectively and successfully carry out the proposed research?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

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

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

Specific to this NOFO:

To what degree does the proposed research have a significant focus on one or more of cerebral small vessel diseases including arteriolosclerosis, CAA, and atherosclerosis (direct impact or downstream effects on small vessels) using multi-faceted approaches? 

To what extent will the proposed research increase understanding of brain small vessel disorders, both cross-sectionally and over time (prodromal and after phenotypic cognitive decline first develops), as well as their relationship to VCID phenotypic and clinical outcomes?

To what degree will the proposed research advance fundamental molecular mechanistic understanding of VCID by using de-identified human tissue and clinical data in parallel with, and mechanistically cross-referencing with, studies in model-based systems including, ideally, both loss of function and gain of function studies?

To what extent does the proposed research have potential to increase fundamental understanding of function and dysfunction of the neurovascular unit, synapses, circuits, and networks in the context of VCID and AD/ADRD overall, including in mixed dementias?

To what extent will the proposed research contribute to foundational knowledge that can promote development of future VCID interventions including for prevention and better clinical outcomes?

To what degree does the proposed research include one or more components designed to increase understanding of interactions between small vessel VCID and at least one other AD/ADRD relevant pathology (for example, but not limited to, the following proteinopathies: beta-amyloid, tau, TDP-43, alpha-synuclein)?

Environment

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

Additional Review Criteria

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

Specific for this NOFO:

Cross-CWOW Coordinating Team (CCCT) Management Plan:

Does the proposed CCCT Management Plan include a suitable strategy, as well as leadership with appropriate scientific and logistical expertise, to manage and coordinate activities that include more than one funded award across the CWOW? Does the CCCT propose a suitable and capable person as the primary point of contact for the CCCT? Is the CCCT Management Plan, overall, acceptable, or unacceptable?

Intellectual Property Strategy:

Is the Intellectual Property Strategy clear, viable for broad sharing of paradigm(s) without undue burden of logistics or cost, and consistent with achieving the goals of the project and of the CWOW program supported by this NOFO? Is the Intellectual Property Strategy, overall, acceptable, or unacceptable?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policies and practices, 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.

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

Applications will be assigned to NINDS as the administrative institute. 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 National Advisory Neurological Disorders and Stroke (NANDS) Council. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

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

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, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, 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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 and 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.”

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the 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.

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. 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 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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: GrantsInfo@nih.gov (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: support@grants.gov

Roderick A. Corriveau

National Institute of Neurological Disorders and Stroke (NINDS)
Email: roderick.corriveau@nih.gov

John Hsiao
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301-496-9350
E-mail: jhsiao@mail.nih.gov

Chief, Scientific Review Branch
National Institute for Neurological Disorders and Stroke (NINDS)
Email: nindsreview.nih.gov@mail.nih.gov

Chief Grants Management Officer
National Institute for Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Philip Smith
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301-555-1212
E-mail: philip.smith2@nih.gov

Section VIII. Other Information

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

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 and 2 CFR Part 200.