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

Frequently Asked Questions (FAQs)

What is NIH PAR-23-023?

PAR-23-023 is a National Institutes of Health (NIH) funding opportunity that supports R01 research projects focused on the basic cellular and molecular biology of "prion-like" behavior in Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD).

What grant mechanism is used for this opportunity?

This opportunity uses the NIH R01 research project grant mechanism.

What is the main scientific focus of the announcement?

The announcement focuses on mechanistic studies of how disease-linked brain proteins misfold, form toxic aggregates, and then spread in a way that resembles classical prion biology. The goal is to understand how "seeded" protein misfolding begins, how it propagates through cells and brain circuits, and how these processes lead to neurotoxicity and circuit-level dysfunction in AD/ADRD.

What does "prion-like" mean in the context of AD/ADRD?

In this context, "prion-like" refers to the idea that certain misfolded proteins associated with AD/ADRD can act as seeds that template the misfolding of normally folded versions of the same protein. This seeded conversion can become self-propagating and may contribute to progressive spread of pathology through tissues and neural circuits.

How does this relate to classical prion diseases like Creutzfeldt-Jakob Disease?

The funding opportunity uses the classical prion framework as a conceptual model. In classical prion diseases, a misfolded seed induces the normal cellular prion protein (PrPC) to adopt a disease-associated conformation (PrPSc), creating a self-propagating cycle of misfolding and aggregation. PAR-23-023 applies that framework to AD/ADRD-associated proteins to understand whether similar seeded conversion and spreading principles drive dementia pathology.

Which proteins are highlighted as having potential prion-like behavior?

The announcement highlights several AD/ADRD-implicated proteins, including (but not limited to) alpha-synuclein, tau, beta-synuclein, and TDP-43, as proteins that may exhibit prion-like features such as seeded misfolding, propagation, and amplification.

What kinds of research questions are responsive to this opportunity?

Responsive projects are expected to move beyond descriptive pathology and instead pinpoint causal mechanisms. Examples of responsive directions include studying structural determinants of seeding competence, identifying cellular machinery involved in uptake/release/trafficking of aggregates, understanding cell-type-specific vulnerabilities, and defining signaling or stress pathways that mediate toxicity once aggregates are present.

What are the three main research themes NIH wants to strengthen in this initiative?

The initiative emphasizes three linked mechanistic themes: (1) aggregate seeding (how an initial misfolded species forms or is introduced and templates further misfolding), (2) aggregate propagation (how misfolded species move within and between cells and spread across brain regions), and (3) downstream toxicity (how aggregation triggers synaptic dysfunction, neuronal injury, neurodegeneration, and circuit-level changes).

What is meant by "aggregate seeding" in this announcement?

Aggregate seeding refers to the earliest events where an initial misfolded protein species forms (or is introduced) and then templates the conversion of normally folded protein into a misfolded, aggregation-prone form, thereby amplifying the pathogenic species.

What is meant by "aggregate propagation" in this announcement?

Aggregate propagation refers to how misfolded and aggregated protein species are maintained over time and how they move within cells, between cells, and across connected brain regions, potentially driving progressive spread of pathology.

What is meant by "downstream toxicity" in this announcement?

Downstream toxicity refers to the molecular pathways and cellular events that translate the presence and spread of aggregates into biological harm, including synaptic dysfunction, neuronal injury, neurodegeneration, and broader disruptions in brain circuitry.

Does NIH expect purely descriptive pathology studies to be competitive?

Based on the description provided, the opportunity is aimed at mechanistic and causal understanding rather than descriptive pathology alone. Proposed work would typically be expected to explain how and why seeding, spread, and toxicity occur at a cellular and molecular level.

Are clinical trials allowed under this funding opportunity?

No. The opportunity is explicitly labeled "Clinical Trial Not Allowed," meaning applicants should not propose a study that meets NIH's definition of a clinical trial.

What is the CFDA number associated with this opportunity?

The CFDA number listed for this opportunity is 93.279.

When was this opportunity created, and what closing date is listed?

The opportunity was created on 2022-07-25, and the original closing date shown is 2022-10-24.

Is an award ceiling provided in the listing?

No award ceiling is specified in the provided information.

Is the expected number of awards specified?

No. The expected number of awards is not specified in the provided information.

How should applicants think about budgeting if no ceiling is provided?

Because an award ceiling is not provided in the listing, the information suggests applicants should rely on standard NIH R01 budget policies and any specific Institute or Center guidance tied to the announcement when planning the budget and project scope.

What types of organizations are eligible to apply?

Eligibility is broad. It includes public and private institutions of higher education; nonprofits (including 501(c)(3) and non-501(c)(3) organizations); for-profit organizations (other than small businesses) and small businesses; and multiple levels of government (state, county, city/township, and special districts). It also includes independent school districts and public housing authorities/Indian housing authorities.

Are tribal organizations eligible to apply?

Yes. The opportunity includes federally recognized Native American tribal governments and non-federally recognized tribal organizations as eligible applicants.

Are minority-serving institutions explicitly included in the eligible applicant list?

Yes. The opportunity explicitly names Alaska Native and Native Hawaiian Serving Institutions, AANAPISI institutions, Hispanic-serving Institutions, Historically Black Colleges and Universities (HBCUs), and Tribally Controlled Colleges and Universities (TCCUs) as eligible applicants.

Are faith-based or community-based organizations eligible?

Yes. Faith-based and community-based organizations are explicitly included as eligible applicants.

Can federal agencies apply?

Yes. Eligible federal agencies are explicitly included in the eligibility list.

Are U.S. territories or possessions eligible?

Yes. U.S. territories or possessions are explicitly included as eligible applicants.

Are non-U.S. (foreign) organizations eligible?

Yes. The eligibility list includes non-domestic (non-U.S.) entities/foreign organizations.

What overall type of research community is this opportunity trying to attract?

Based on the provided description, the opportunity is positioned to attract a wide range of basic and translational neuroscience and cell biology research groups working on protein misfolding and neurodegeneration, with an emphasis on mechanistic insight into prion-like seeding, spread, and toxicity in AD/ADRD.

What is the unifying requirement across proposed projects?

The unifying requirement described is that the proposed work must directly advance mechanistic insight into prion-like aggregate seeding, propagation/spread, and the biological basis of neurotoxicity in Alzheimer's disease and related dementias.