Deciphering the Impact of RNA Modifications on Brain Aging and AD/ADRD (R21 Clinical Trial Not Allowed) | RFA AG 25 023

Opportunity Information: Apply for RFA AG 25 023

The National Institutes of Health (NIH) is soliciting exploratory and developmental research applications under the R21 mechanism through the funding opportunity titled "Deciphering the Impact of RNA Modifications on Brain Aging and AD/ADRD (R21 Clinical Trial Not Allowed)" (Funding Opportunity Number: RFA-AG-25-023). The overall goal is to accelerate early-stage, innovative work that clarifies how RNA modifications shape molecular changes in the aging brain and how those changes contribute to the development and progression of Alzheimer’s disease (AD) and Alzheimer’s disease-related dementias (ADRD). In this context, ADRD is defined broadly and explicitly includes Lewy body dementia (LBD), frontotemporal dementia (FTD), vascular cognitive impairment/dementia (VCI/D), and mixed dementias, reflecting NIH’s interest in mechanisms that may be shared across disorders or that distinguish one dementia subtype from another.

This NOFO is centered on RNA modifications, meaning chemical changes to RNA molecules that can influence RNA stability, localization, splicing, translation, and RNA-protein interactions. The emphasis is not simply on cataloging modifications, but on understanding their functional consequences and the mechanisms by which they affect brain aging and disease pathways relevant to AD/ADRD. The program aims to "catalyze" research that elucidates both the molecular landscape of these modifications in relevant brain contexts and the downstream biological implications, such as impacts on neuronal function, glial biology, synaptic integrity, stress responses, proteostasis, inflammation, vascular contributions to cognitive impairment, or other processes tied to neurodegeneration and cognitive decline.

A key boundary in the scope is that proposed studies should focus on functional characterization and mechanistic investigation of previously identified RNA modifications. In practical terms, this signals that applications are expected to build on existing observations (for example, a known modification at specific transcripts, in particular cell types, or in disease-relevant regions) and move toward testing what that modification does and how it drives or modifies pathological processes. The R21 format is designed for exploratory work, so projects can be high-risk or conceptually novel, but they still need a clear mechanistic angle and a plan to generate decisive evidence rather than purely descriptive datasets.

The award is categorized as discretionary funding and uses the grant instrument, with the activity area in health and the CFDA (Assistance Listing) number 93.866. The maximum award amount listed is $275,000 (award ceiling). The original application closing date is 2024-11-01. The NOFO is explicitly "Clinical Trial Not Allowed," meaning applications should not propose prospective human intervention studies that meet NIH’s definition of a clinical trial. Applicants can generally still consider use of existing human data and biospecimens, observational analyses, postmortem tissues, or model systems, as long as the work does not cross into clinical trial territory.

Eligibility is broad and includes many organizational types. Domestic eligible applicants include state, county, city/township, and special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; federally recognized Native American tribal governments; Native American tribal organizations that are not federally recognized tribal governments; public housing authorities/Indian housing authorities; nonprofits with and without 501(c)(3) status (excluding institutions of higher education in those nonprofit categories); for-profit organizations other than small businesses; and small businesses. The announcement also highlights additional eligible applicant categories such as Alaska Native and Native Hawaiian Serving Institutions; Asian American, Native American, and Pacific Islander Serving Institutions (AANAPISIs); Hispanic-serving Institutions; Historically Black Colleges and Universities (HBCUs); Tribally Controlled Colleges and Universities (TCCUs); faith-based or community-based organizations; eligible federal agencies; regional organizations; U.S. territories or possessions; and non-domestic (non-U.S.) entities/foreign organizations. This wide eligibility reflects an intent to draw innovative ideas from a diverse set of research environments and community contexts, including international groups where appropriate.

In short, this NIH R21 opportunity is aimed at jump-starting mechanistic research that connects specific, already-documented RNA modifications to biological function in brain aging and to pathogenic processes in AD and related dementias. Competitive projects will be positioned to explain not only where RNA modifications occur, but why they matter, how they alter cellular and circuit-level biology, and how those effects might help explain vulnerability or resilience in aging and AD/ADRD-relevant neurodegenerative pathways, all within a non-clinical-trial framework.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Deciphering the Impact of RNA Modifications on Brain Aging and AD/ADRD (R21 Clinical Trial Not Allowed)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.866.
• This funding opportunity was created on 2024-07-31.
• Applicants must submit their applications by 2024-11-01. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $275,000.00 in funding.
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501 (c) (3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501 (c) (3) status with the IRS, other than institutions of higher education, Private institutions of higher education, For-profit organizations other than small businesses, Small businesses, Others.

Apply for RFA AG 25 023

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