Cellular and Molecular Mechanisms of Prion-Like Aggregate Seeding, Propagation, and Neurotoxicity in AD/ADRD (R01 Clinical Trial Not Allowed) | PAR 23 023

Opportunity Information: Apply for PAR 23 023

The National Institutes of Health (NIH) funding opportunity PAR-23-023 supports R01 research projects focused on the basic cellular and molecular biology behind "prion-like" behavior in Alzheimers disease and Alzheimers disease-related dementias (AD/ADRD). The core scientific idea behind the announcement is that many dementias share a common pathological theme: specific brain proteins misfold, clump together, and accumulate as toxic aggregates. In classical prion diseases such as Creutzfeldt-Jakob Disease, this process is driven by a well-defined mechanism in which the normal cellular prion protein (PrPC) is forced into a disease-associated shape (PrPSc) after interacting with a misfolded "seed." That seed-induced conformational conversion then becomes self-propagating, spreading and amplifying until aggregates build up in the central nervous system and ultimately contribute to neuronal dysfunction and death.

This opportunity takes that prion framework and applies it to AD/ADRD, where multiple disease-linked proteins are increasingly thought to act in a similar way. The announcement highlights that several proteins implicated in these dementias, including but not limited to alpha-synuclein, tau, beta-synuclein, and TDP-43, may share structural and behavioral features with prion protein in the sense that misfolded forms can "seed" the misfolding of normally folded protein, propagate through cells and brain circuits, and drive progressive pathology. NIH is looking for studies that dig into how these conversion events begin at the molecular level, how they are sustained and spread over time, and what cellular responses or failures convert aggregate propagation into neurotoxicity and circuit-level brain changes.

From a research scope standpoint, the initiative is aimed at strengthening mechanistic understanding of three linked themes: (1) aggregate seeding, meaning how an initial misfolded species forms or is introduced and then templates further misfolding; (2) aggregate propagation, meaning how these species move within and between cells and how pathology spreads across brain regions; and (3) downstream toxicity, meaning the specific molecular pathways and cellular events that translate aggregation into synaptic dysfunction, neuronal injury, neurodegeneration, and broader alterations in brain circuitry. In practice, projects responsive to this announcement would typically be expected to move beyond descriptive pathology and instead pinpoint causal mechanisms, such as the structural determinants of seeding competence, the cellular machinery that enables uptake/release/trafficking of aggregates, cell-type-specific vulnerabilities, and the signaling or stress pathways that mediate toxicity once aggregates are present.

Administratively, this is an NIH discretionary grant using the R01 mechanism, and it is explicitly labeled "Clinical Trial Not Allowed," meaning applicants should not propose a study that meets NIH's definition of a clinical trial. The activity category is listed under education and health, and the CFDA number provided is 93.279. The original closing date shown in the source information is 2022-10-24, and the opportunity was created on 2022-07-25. An award ceiling and expected number of awards are not specified in the provided listing, which generally means applicants should rely on standard NIH R01 budget policies and the specific Institute or Center guidance associated with the announcement when planning budgets and scope.

Eligibility is broad and includes many common applicant organizations such as public and private institutions of higher education, nonprofits (including 501(c)(3) and non-501(c)(3) entities), for-profit organizations (other than small businesses) and small businesses, and various levels of government (state, county, city/township, special districts), as well as independent school districts and public housing authorities/Indian housing authorities. It also includes federally recognized Native American tribal governments and non-federally recognized tribal organizations. The announcement also explicitly calls out additional eligible applicants such as Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISI), 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 even non-domestic (non-U.S.) entities/foreign organizations. Overall, the opportunity is positioned to attract a wide range of basic and translational neuroscience and cell biology groups working on protein misfolding and neurodegeneration, with the unifying requirement that the proposed work directly advances mechanistic insight into prion-like aggregate seeding, spread, and the biological basis of neurotoxicity in AD/ADRD.

• The National Institutes of Health in the education, health sector is offering a public funding opportunity titled "Cellular and Molecular Mechanisms of Prion-Like Aggregate Seeding, Propagation, and Neurotoxicity in AD/ADRD (R01 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 2022-07-25.
• Applicants must submit their applications by 2022-10-24. (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 PAR 23 023

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