Pilot Projects Investigating Understudied Proteins Associated with Rare Diseases (R03 Clinical Trial Not Allowed) | PAR 25 122

Opportunity Information: Apply for PAR 25 122

The NIH funding opportunity "Pilot Projects Investigating Understudied Proteins Associated with Rare Diseases (R03 Clinical Trial Not Allowed)" (PAR-25-122) is a discretionary grant program designed to spark early-stage research on proteins that are still poorly characterized but have known links to rare diseases. The central aim is to help researchers take practical first steps toward understanding what these proteins do, how they contribute to rare disease biology, and why they might matter as potential therapeutic targets. This program is positioned as a jumpstart mechanism: it is meant to fund focused pilot studies that can produce preliminary data and/or create enabling tools that make deeper, future work possible.

A defining feature of the opportunity is that applicants must work on an eligible set of "understudied proteins" provided by the program. These proteins are described as belonging to druggable protein families and having a known association with a rare disease, but they have not been explored enough to clearly define their biochemical function, biological role, or disease relevance. In other words, the NIH is trying to close a common gap in biomedical research where many disease-associated genes and proteins exist in databases and genetic studies, yet the field lacks the kind of foundational experimental evidence needed to confidently pursue mechanism-based therapy development. The NOFO emphasizes basic biochemical and/or biological work, meaning the intended projects are the kinds of rigorous, targeted studies that clarify function, pathways, interactions, and disease context rather than large, multi-year translational programs.

Because this is an R03 mechanism, the award is structured to support smaller, time-limited pilot efforts. The listed award ceiling is $100,000, reinforcing that this is meant to fund tightly scoped projects that deliver concrete outputs such as early experimental validation, proof-of-concept findings, assay development, reagents, or other tools that enable subsequent R01-level investigations. The funding is explicitly marked "Clinical Trial Not Allowed," which signals that the supported research should not involve prospective assignment of human participants to interventions to assess health-related outcomes. The work should stay in the realm of preclinical and foundational research, such as molecular characterization, cell-based functional studies, biochemical assays, pathway mapping, genetic perturbation experiments, or development of experimental platforms that illuminate protein function in a rare disease setting.

The program is broadly open in terms of who can apply, reflecting NIH's interest in drawing on a wide range of scientific capabilities and institutional contexts. Eligible applicants include many domestic public-sector entities (state, county, city or township governments; special district governments; independent school districts), higher education institutions (public/state-controlled and private), tribal governments (federally recognized) and tribal organizations (including those other than federally recognized tribal governments), public housing authorities/Indian housing authorities, and a wide range of nonprofit organizations (with or without 501(c)(3) status). For-profit organizations are also eligible (other than small businesses), as are small businesses and other applicant types. The NOFO additionally highlights several categories of organizations as eligible or included among eligible applicants, such as Historically Black Colleges and Universities (HBCUs), Hispanic-serving Institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, and Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), as well as faith-based or community-based organizations and eligible federal agencies. This breadth suggests the NIH wants to encourage participation from institutions with diverse missions and perspectives, including those that may bring unique disease-community ties or specialized technical strengths.

At the same time, there are clear boundaries around foreign participation. Non-domestic (non-U.S.) entities (foreign organizations) are not eligible to apply as applicant institutions, and non-domestic components of U.S. organizations are also not eligible to apply. However, the NOFO allows foreign components as defined by the NIH Grants Policy Statement, meaning a U.S.-based applicant can, where justified and compliant with NIH rules, include certain foreign elements as part of the project (for example, specific collaborations, resources, or activities conducted abroad), even though a foreign organization cannot be the primary applicant.

From an administrative standpoint, the opportunity is run by the National Institutes of Health and falls under health-related funding activity categories. The listing includes CFDA numbers 93.121, 93.173, 93.242, 93.350, 93.853, and 93.855, indicating it aligns with multiple NIH program areas. The opportunity was created on 2024-10-28, and the original closing date is 2027-11-16, giving applicants a multi-year window to plan and submit proposals under this announcement. While the listing does not specify the number of expected awards, the intent is clearly to seed multiple pilot projects that can collectively expand the research community's knowledge base around these neglected, disease-linked proteins.

Overall, this NOFO is best understood as targeted seed funding for rigorous, early experimental work that will make rare-disease-associated but poorly understood proteins more tractable to the broader research and drug discovery ecosystem. The NIH is essentially paying for the hard but necessary first-mile science: generating data, building assays and tools, and establishing biological credibility for proteins that are promising yet still mostly unexplored, with the longer-term goal of enabling stronger future applications and accelerating progress toward therapies for rare diseases.

• The National Institutes of Health in the health sector is offering a public funding opportunity titled "Pilot Projects Investigating Understudied Proteins Associated with Rare Diseases (R03 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): 93.121, 93.173, 93.242, 93.350, 93.853, 93.855.
• This funding opportunity was created on 2024-10-28.
• Applicants must submit their applications by 2027-11-16.
• Each selected applicant is eligible to receive up to $100,000.00 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.

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