Pathogenic Mechanisms influencing Blood Brain Barrier function in HIV and Substance Use Disorders (R01 Clinical Trial Optional) | RFA DA 23 012

Opportunity Information: Apply for RFA DA 23 012

The National Institutes of Health (NIH) funding opportunity RFA-DA-23-012, titled "Pathogenic Mechanisms influencing Blood Brain Barrier function in HIV and Substance Use Disorders (R01 Clinical Trial Optional)," supports research focused on how HIV and addictive substances interact to damage or alter the blood brain barrier (BBB). The central idea behind the announcement is that the BBB is not just a passive wall around the brain; it is a dynamic interface that can be directly targeted by HIV-related processes and by many commonly misused substances. When BBB integrity is weakened, it can change how much virus and how much drug exposure reaches the brain, shaping neurological outcomes and complicating both HIV treatment and substance use disorder (SUD) management.

A major scientific driver for this initiative is the way HIV can access the central nervous system through the BBB. The announcement highlights that HIV-infected monocytes and macrophages can cross the BBB using paracellular routes (moving between cells) or transcellular routes (moving through cells). In addition to infected cells acting as "carriers," HIV viral proteins themselves may disrupt BBB structure by attacking astrocytes and tight junctions, which are key molecular components that maintain the barrier's seal and selective permeability. When these structures are compromised, both viral material and substances of abuse may enter the brain more readily, potentially escalating neuroinflammation, neuronal injury, and other CNS complications associated with HIV.

The opportunity also emphasizes that many substances of abuse can independently cause BBB dysfunction. In practice, this means the BBB may be stressed from multiple directions at once: HIV-driven immune cell trafficking and viral protein toxicity on one side, and drug-induced inflammatory, oxidative, or vascular effects on the other. Because the BBB helps regulate concentrations of both virus and drugs in the brain, the FOA stresses the need to define the mechanisms by which HIV infection in combination with substance use alters BBB function and integrity, and to determine the downstream consequences of those changes. This includes clarifying the molecular and cellular pathways involved in BBB disruption, how permeability changes over time, and how these processes affect viral persistence and neuropathology.

In terms of what NIH is looking to fund, the FOA calls for innovative research that expands understanding of basic molecular mechanisms governing virus mobilization across the BBB and BBB pathology in the context of HIV and SUD. This can include mechanistic studies of endothelial cells, pericytes, astrocytes, immune cell migration, tight junction regulation, and inflammatory signaling that influence barrier permeability. Beyond studying the damage itself, the announcement explicitly encourages development and testing of novel BBB models. The intent is for researchers to build or refine experimental systems that better predict or measure how pharmacological treatments and immunotherapies reach the CNS, how they might be optimized for delivery across a compromised or altered BBB, and how strategies could be designed to suppress HIV replication within the CNS. The "Clinical Trial Optional" designation indicates that applications may include clinical trials but are not required to do so; applicants can propose basic, translational, or clinical work as appropriate to the research questions.

Administratively, this is an R01 grant mechanism under NIH, categorized as a discretionary grant in the broad education and health activity area, with CFDA number 93.279. The original closing date listed for this opportunity was 2023-08-11, and the creation date was 2022-04-26. While an award ceiling and expected number of awards are not specified in the provided text, the structure aligns with an NIH research project grant intended to support substantial multi-year research programs.

Eligibility is broad and includes many types of U.S.-based organizations: state, county, and local governments; 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; other Native American tribal organizations; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status (other than institutions of higher education); for-profit organizations other than small businesses; and small businesses. The FOA also points out additional eligible applicant categories such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Alaska Native and Native Hawaiian Serving Institutions, AANAPISIs, Tribally Controlled Colleges and Universities (TCCUs), faith-based or community-based organizations, regional organizations, eligible federal agencies, and U.S. territories or possessions. Foreign institutions and other non-U.S. entities are not eligible to apply directly, and non-domestic components of U.S. organizations are also not eligible; however, foreign components are allowed as defined by the NIH Grants Policy Statement, meaning a U.S. applicant can include certain international collaborations or elements when justified and compliant with NIH policy.

Overall, the grant opportunity is aimed at closing critical gaps in how the BBB is compromised by the combined pressures of HIV infection and substance use, and at enabling better therapeutic strategies by improving BBB-relevant models and understanding of CNS drug and immunotherapy delivery. The long-term public health relevance is tied to reducing neurological complications of HIV, improving outcomes for people with co-occurring HIV and SUD, and supporting approaches that can better control or suppress HIV within the CNS where the BBB plays a central gatekeeping role.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Pathogenic Mechanisms influencing Blood Brain Barrier function in HIV and Substance Use Disorders (R01 Clinical Trial Optional)" 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 2022-04-26.
• Applicants must submit their applications by 2023-08-11. (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.

Apply for RFA DA 23 012

[Watch] Creating a grant proposal using the step-by-step wizard inside the applicant portal: