Opportunity Information: Apply for RFA DA 25 063
The funding opportunity titled "Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 Clinical Trial Not Allowed)" (Funding Opportunity Number RFA-DA-25-063) is a National Institutes of Health (NIH) discretionary grant focused on neuroimmune mechanisms at the intersection of HIV infection and substance use disorder. Its central purpose is to push the field beyond broad, whole-brain or mixed-cell signals by producing highly specific molecular maps of microglia, the brain's resident immune cells, under conditions where HIV and SUD occur together. The intent is not just descriptive profiling, but using those data to build interaction networks and then test mechanistic hypotheses about how HIV-harboring microglia may drive or worsen the types of neurological damage and dysfunction that appear in people living with both HIV and SUD.
Scientifically, the announcement is aimed at generating brain region- and cell-type-specific microglial protein profiles in the context of HIV and SUD. That emphasis on protein profiles matters because proteins are closer to functional biology than gene expression alone: they reflect signaling activity, immune activation states, metabolic shifts, synaptic remodeling, and other processes that microglia use to influence neurons and brain circuits. By specifying brain region and cell type, the opportunity highlights that microglial behavior is not uniform across the brain, and that relevant disease mechanisms may be localized to particular circuits affected by HIV and commonly used substances. The expected outcome is a set of molecular profiles that can be translated into interaction networks (for example, pathways and protein-protein relationships) that clarify which microglial processes are most disrupted or most causally linked to neuropathology in comorbidity.
A key second step in the program is mechanistic work that leverages the generated profiles and networks to establish how HIV-harboring microglia contribute specifically to neuropathologies encountered with comorbid HIV and SUD. In practical terms, this means applicants are expected to move from identifying patterns to explaining cause-and-effect, such as pinpointing microglial pathways that become uniquely harmful when both HIV-related factors and substance-related exposures are present. The focus on "HIV-harboring microglia" suggests interest in persistence of HIV in the central nervous system, microglia as a potential reservoir, and how that reservoir status might alter inflammatory signaling, synaptic pruning, neuronal support functions, or responses to drugs of abuse in ways that amplify cognitive, behavioral, or neurodegenerative outcomes.
From a mechanism and structure standpoint, this is an R61/R33 phased innovation award and it explicitly states "Clinical Trial Not Allowed." The R61/R33 format typically supports a milestone-driven progression where an initial phase (R61) establishes feasibility, generates key datasets, or proves an approach, and a second phase (R33) expands and deepens the work once predefined benchmarks are met. Even without going into specific milestone language from the full FOA text, the overall design implies a pipeline: first build the region- and cell-type-resolved microglial proteomic resources in HIV/SUD contexts, then use those resources to validate networks and test mechanisms with rigorous experimental approaches. The clinical trial restriction indicates the funded research should not be structured as a prospective interventional study in humans designed to evaluate health outcomes, though it can still support many forms of non-trial human-based research depending on NIH definitions (for instance, analysis of existing specimens, observational studies, or laboratory-based investigations).
Administratively, the opportunity is categorized under Education and Health funding activity and is associated with CFDA number 93.279. The agency is the NIH, and the original closing date is listed as 2025-08-14. The public listing does not specify an award ceiling or the expected number of awards, which usually means applicants need to consult the full FOA for budget guidance, anticipated award counts, and any institute-specific limits or preferences.
Eligibility is broad and intentionally inclusive, spanning government entities, academic institutions, nonprofits, and the private sector. Eligible applicants include state, county, city or township governments; special district governments; independent school districts; public and state-controlled institutions of higher education; private institutions of higher education; public housing authorities and Indian housing authorities; Native American tribal governments (federally recognized) as well as Native American tribal organizations that are not federally recognized; 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. In addition to these standard categories, the announcement explicitly calls out other eligible applicant types such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American 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, U.S. territories or possessions, regional organizations, and non-domestic (non-U.S.) entities (foreign organizations). That expanded list signals an interest in encouraging participation from a wide range of institutions and communities, including those that may be closely connected to populations disproportionately affected by HIV and substance use, as well as organizations that can contribute unique resources, cohorts, tissue repositories, analytic platforms, or specialized neuroscience and proteomics expertise.
In summary, this NIH grant opportunity is designed to produce detailed, region- and cell-type-resolved microglial proteomic datasets in HIV and SUD comorbidity and to use those datasets to build and validate interaction networks that explain disease mechanisms. It prioritizes mechanistic insight into how microglia that harbor HIV could contribute to the neurological complications seen when HIV and SUD co-occur, using a phased R61/R33 structure to move from feasibility and resource generation to deeper mechanistic testing, while keeping the work outside the boundaries of NIH-defined clinical trials.Apply for RFA DA 25 063
- The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 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): 93.279.
- This funding opportunity was created on 2024-08-23.
- Applicants must submit their applications by 2025-08-14. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
- 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.
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Frequently Asked Questions (FAQs)
What is the title and funding opportunity number for this grant?
The opportunity is titled "Microglial Pathophysiology in Comorbid Substance Use Disorder (SUD) and HIV (R61/R33 Clinical Trial Not Allowed)" and the Funding Opportunity Number is RFA-DA-25-063.
Which agency is offering this funding opportunity?
This is a National Institutes of Health (NIH) discretionary grant opportunity.
What is the main scientific focus of this opportunity?
The focus is on neuroimmune mechanisms at the intersection of HIV infection and substance use disorder (SUD), specifically centered on microglia (the brain's resident immune cells) in the setting where HIV and SUD co-occur.
What is the central purpose of the research being supported?
The central purpose is to move beyond broad whole-brain or mixed-cell signals by generating highly specific molecular maps of microglia under comorbid HIV and SUD conditions, then using those data to build interaction networks and test mechanistic hypotheses about neurological damage and dysfunction.
Why does the opportunity emphasize microglia?
Microglia are the brain's resident immune cells and are implicated in immune activation, signaling, synaptic remodeling, metabolic shifts, and other processes that can influence neurons and brain circuits. The opportunity is specifically interested in how microglia contribute to neuropathology when HIV and SUD are present together.
What does the opportunity mean by moving beyond "whole-brain" or "mixed-cell" signals?
It means the program is intended to generate more precise, cell-type-specific and brain-region-specific molecular information, rather than relying on averaged signals that can obscure microglia-specific mechanisms.
What types of molecular data are especially emphasized?
The announcement emphasizes generating brain region- and cell-type-specific microglial protein profiles in the context of HIV and SUD.
Why are protein profiles specifically called out?
Protein profiles are emphasized because proteins are closer to functional biology than gene expression alone and can reflect signaling activity, immune activation states, metabolic shifts, synaptic remodeling, and related functional processes.
Does the opportunity require brain region-specific analysis?
Yes. The opportunity highlights that microglial behavior is not uniform across the brain and calls for brain region-specific profiling to capture mechanisms that may be localized to circuits affected by HIV and commonly used substances.
Does the opportunity also require cell-type-specific analysis?
Yes. A key intent is to generate microglia-specific profiles (rather than mixed-cell profiles) to clarify microglial mechanisms in HIV/SUD comorbidity.
What is meant by "interaction networks" in this context?
The expected molecular profiles are intended to be translated into interaction networks such as pathways and protein-protein relationships that help identify which microglial processes are most disrupted or most causally linked to neuropathology in comorbidity.
Is the goal purely descriptive profiling, or is mechanistic work expected?
Mechanistic work is expected. The intent is not just descriptive profiling; applicants are expected to use the resulting profiles and networks to test mechanistic hypotheses and establish cause-and-effect relationships relevant to comorbid HIV and SUD neuropathology.
What does the opportunity say about "HIV-harboring microglia"?
The program signals interest in microglia as a potential HIV reservoir in the central nervous system and in understanding how HIV-harboring microglia may drive or worsen neurological damage and dysfunction when HIV and SUD co-occur.
What kinds of microglial functions or processes are highlighted as relevant?
The description references inflammatory signaling, synaptic pruning, neuronal support functions, responses to drugs of abuse, immune activation states, metabolic shifts, and synaptic remodeling as examples of microglial processes that may be implicated.
What are the expected outcomes of the funded research?
Expected outcomes include detailed brain region- and cell-type-resolved microglial proteomic datasets in HIV/SUD contexts, derived interaction networks (e.g., pathways and protein relationships), and mechanistic validation work that clarifies how HIV-harboring microglia contribute to neurological complications in comorbidity.
What grant mechanism is being used?
This opportunity uses the R61/R33 phased innovation award mechanism.
How does the R61/R33 phased structure work in general terms (based on the listing)?
In general terms, the structure is milestone-driven: an initial phase (R61) is intended to establish feasibility and/or generate key datasets or resources, and a second phase (R33) expands and deepens the work once predefined benchmarks are met.
What is the implied research "pipeline" across the two phases?
The implied pipeline is: first, build region- and cell-type-resolved microglial proteomic resources in HIV/SUD contexts; second, use those resources to validate networks and test mechanistic hypotheses using rigorous experimental approaches.
Are clinical trials allowed under this funding opportunity?
No. The opportunity explicitly states "Clinical Trial Not Allowed."
What does "Clinical Trial Not Allowed" imply about the types of studies that can be supported?
It indicates the funded research should not be structured as a prospective interventional study in humans designed to evaluate health outcomes. The description notes that many forms of non-trial human-based research may still be possible depending on NIH definitions (for example, analysis of existing specimens, observational studies, or laboratory-based investigations).
What funding activity category is associated with this opportunity?
The listing categorizes the opportunity under Education and Health.
What CFDA number is associated with this opportunity?
The associated CFDA number is 93.279.
What is the listed closing date?
The original closing date listed is 2025-08-14.
Is the award ceiling stated in the public listing provided?
No. The public listing described does not specify an award ceiling.
Does the listing state the expected number of awards?
No. The public listing described does not specify the expected number of awards.
What should applicants do about missing budget or award count details?
Because the public listing does not specify an award ceiling or expected number of awards, applicants would typically need to consult the full FOA for budget guidance, anticipated award counts, and any institute-specific limits or preferences.
Who is eligible to apply?
Eligibility is broad and includes government entities, academic institutions, nonprofits, and the private sector, including small businesses and for-profit organizations (other than small businesses) as listed.
Which government entities are eligible?
Eligible government applicants include state governments; county governments; city or township governments; and special district governments.
Are school districts eligible?
Yes. Independent school districts are listed as eligible applicants.
Are public and private universities eligible?
Yes. Public and state-controlled institutions of higher education and private institutions of higher education are listed as eligible.
Are nonprofits eligible, including those without 501(c)(3) status?
Yes. Nonprofits with 501(c)(3) status and nonprofits without 501(c)(3) status are included as eligible categories (excluding institutions of higher education within those nonprofit categories as stated in the listing).
Are for-profit organizations eligible?
Yes. For-profit organizations other than small businesses are listed as eligible, and small businesses are also listed as eligible.
Are public housing authorities eligible?
Yes. Public housing authorities and Indian housing authorities are listed as eligible.
Are Native American tribal governments and tribal organizations eligible?
Yes. The listing includes Native American tribal governments (federally recognized) and Native American tribal organizations that are not federally recognized.
Are minority-serving institutions and other specifically named institution types eligible?
Yes. The listing explicitly calls out Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), Tribally Controlled Colleges and Universities (TCCUs), and additional institution types.
Are faith-based or community-based organizations eligible?
Yes. Faith-based or community-based organizations are explicitly included in the expanded eligibility list.
Are federal agencies eligible applicants?
Yes. Eligible federal agencies are listed as eligible applicant types.
Are U.S. territories and possessions eligible?
Yes. U.S. territories or possessions are listed as eligible applicant types.
Are regional organizations eligible?
Yes. Regional organizations are included in the expanded eligibility list.
Are non-U.S. (foreign) organizations eligible to apply?
Yes. The listing explicitly includes non-domestic (non-U.S.) entities (foreign organizations) as eligible.
What overarching research problem is this opportunity trying to address?
The opportunity aims to clarify microglial mechanisms that may underlie neurological damage and dysfunction seen in people living with both HIV and SUD, with a particular emphasis on pinpointing microglial pathways that become uniquely harmful under combined HIV-related and substance-related conditions.
What is the main takeaway about the program's priorities?
The program prioritizes (1) highly specific, brain-region and microglia-resolved proteomic profiling in HIV/SUD comorbidity, (2) translating those profiles into interaction networks, and (3) mechanistic testing to establish how HIV-harboring microglia contribute to comorbidity-related neuropathology, within an R61/R33 phased structure and outside NIH-defined clinical trials.
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