Opportunity Information: Apply for RFA NS 19 015
Apply for RFA NS 19 015
- The National Institutes of Health in the health sector is offering a public funding opportunity titled "Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3 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): 93.853, 93.866.
- This funding opportunity was created on 2019-03-06.
- Applicants must submit their applications by 2019-05-06. (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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Opportunity Summary:
The NIH grant opportunity "Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3 Clinical Trial Not Allowed)" (RFA-NS-19-015) is a cooperative agreement designed to push promising, human-relevant therapeutic targets for ADRDs through a more rigorous and practical stage of validation before groups invest heavily in drug development. The central idea is to reduce risk in the early translational pipeline by requiring applicants to move beyond target discovery and instead deliver convincing functional evidence that a newly identified target or pathway actually changes disease-relevant biology when it is modulated. The targets proposed must already have a strong starting rationale based on human data, specifically tissue expression findings or genetic evidence generated from human samples, rather than being purely hypothesis-driven from animal work alone.
The funding mechanism is structured in two linked phases, UG3 followed by UH3, with milestones that determine progression. The UG3 phase supports up to two years of preparatory and enabling work that often determines whether a target is realistically testable in a way that will matter for later therapy development. During UG3, teams are expected to build or refine the customized tools and experimental foundations needed to manipulate the target candidate (for example, methods to increase or decrease expression, inhibit or enhance activity, or otherwise perturb the pathway) and then to monitor the downstream functional consequences in appropriate experimental systems. This can include developing new or improved cellular systems, tissue-based assays, or in vivo disease models, along with protocols and measurement strategies that can reliably capture biologically meaningful changes tied to ADRD mechanisms.
If the UG3 period demonstrates technical feasibility and the project meets the predefined milestones, the project transitions to the UH3 phase. The UH3 period is focused on careful, reproducible measurement and confirmation, with an emphasis on cross-validation across different modalities and across collaborating laboratories. A major expectation is that results will not depend on a single lab, a single assay, or a single readout, but will instead be tested and confirmed using multiple approaches. This phase explicitly aligns with NIH rigor and reproducibility standards, meaning projects should incorporate practices like robust experimental design, appropriate controls, clear statistical planning, transparent reporting, and replication or independent confirmation where feasible. The overall goal is to produce a strong, reproducible functional validation package that can justify subsequent translational steps such as lead discovery or preclinical therapeutic development, while also helping the field avoid chasing targets that look interesting on paper but fail under rigorous functional testing.
The scope of dementias covered is broad across the ADRD landscape, rather than being limited to one subtype. Applications may focus on frontotemporal degeneration (FTD), Lewy body dementias (including dementia with Lewy bodies, DLB), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias, including the diagnostic and biological challenges associated with multiple-etiology dementias (MED). This breadth signals that NIH is looking for a pipeline of validated targets across diverse disease mechanisms, including neurodegenerative, synucleinopathy-related, tau-related, vascular, and mixed-pathology presentations.
The announcement emphasizes collaboration as a core feature rather than an optional add-on. Applicants are expected to propose substantial teamwork among independent laboratories, which fits the cross-validation requirement and is meant to strengthen confidence that the observed effects of target modulation are real and generalizable. Because the award is a cooperative agreement, recipients should also expect a closer working relationship with NIH compared with a standard grant, typically involving shared oversight, milestone-driven management, and coordination to ensure the project stays aligned with the FOA's validation and reproducibility goals.
This FOA explicitly does not allow clinical trials, keeping the focus on preclinical and mechanistic validation work rather than testing interventions in human participants. It sits within NIH's health research mission and is listed under CFDA numbers 93.853 and 93.866. The eligible applicant pool is wide and includes many types of U.S.-based organizations such as state, county, and local governments; public and private institutions of higher education; federally recognized tribal governments and certain tribal organizations; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status; for-profit organizations (other than small businesses) as well as small businesses; and other eligible entities. The FOA also calls out additional eligible applicant categories often associated with broadening participation, including 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), along with faith-based or community-based organizations and U.S. territories or possessions. At the same time, it places firm limits on foreign involvement: non-U.S. entities and foreign institutions are not eligible to apply, non-domestic components of U.S. organizations are not eligible, and foreign components as defined by NIH policy are not allowed.
In practical terms, a competitive application under this opportunity would lay out a full UG3-to-UH3 plan with clear milestones, showing how the team will (1) build the tools and models needed to perturb the target in disease-relevant systems, (2) measure meaningful functional outcomes linked to ADRD biology, and then (3) replicate and cross-check those findings across labs and methods under strong rigor and reproducibility practices. The end product NIH is trying to buy with this FOA is not just another list of interesting targets, but a set of thoroughly stress-tested targets with solid functional evidence in models and assays that connect back to human genetic or expression signals, positioning the best candidates for faster and more confident therapeutic development later on.
FAQs: Functional Target Validation for Alzheimer's Disease-Related Dementias (ADRDs) (UG3/UH3 Clinical Trial Not Allowed) - RFA-NS-19-015
What is the purpose of this NIH funding opportunity?
This opportunity supports projects that take promising, human-relevant therapeutic targets for Alzheimer's disease-related dementias (ADRDs) and push them through a more rigorous, practical stage of functional validation before major investments are made in drug development. The main goal is to reduce early translational risk by requiring applicants to produce convincing evidence that modulating a target or pathway changes disease-relevant biology in meaningful ways.
What does "functional target validation" mean in this FOA?
In this context, functional validation means going beyond target discovery and showing that when the target is perturbed (for example, increased, decreased, inhibited, or enhanced), there are measurable downstream effects that matter to ADRD biology. The FOA emphasizes evidence that is practical for translation and not dependent on a single assay, a single readout, or a single laboratory.
What kind of starting evidence does NIH expect for proposed targets?
Proposed targets must already have a strong rationale based on human data. Specifically, the FOA highlights human tissue expression findings or genetic evidence generated from human samples. Targets should not be based only on hypothesis-driven animal work without a human-data anchor.
What activity does NIH want to avoid funding under this announcement?
The FOA is not intended to fund projects that stop at listing interesting targets or pathways. Instead, it is designed to support projects that deliver a stress-tested package of functional evidence demonstrating that target modulation changes disease-relevant biology in reproducible ways.
What funding mechanism is used (UG3/UH3), and what does that mean?
This is a two-phase, milestone-driven cooperative agreement. The project begins in the UG3 phase and may transition to the UH3 phase if predefined milestones are met. The linked phases are intended to move a project from tool-building and feasibility into rigorous confirmation and cross-validation.
How long is the UG3 phase and what is it for?
The UG3 phase supports up to two years of preparatory and enabling work. During UG3, teams are expected to build or refine tools and experimental foundations needed to manipulate the target and measure functional consequences in appropriate systems.
What types of work are expected during the UG3 phase?
UG3 activities may include developing methods to perturb the target (such as increasing/decreasing expression or inhibiting/enhancing activity), building or improving cellular systems, tissue-based assays, or in vivo disease models, and establishing protocols and measurement strategies that can reliably capture meaningful biological changes tied to ADRD mechanisms.
What triggers the transition from UG3 to UH3?
Transition depends on demonstrating technical feasibility and meeting predefined milestones established for the UG3 period. If those milestones are achieved, the project can move into the UH3 phase.
What is the focus of the UH3 phase?
UH3 is focused on careful, reproducible measurement and confirmation of functional effects. A key expectation is cross-validation across different modalities and across collaborating laboratories, so results are not reliant on a single lab, assay, or readout.
How does this FOA address rigor and reproducibility?
The UH3 phase explicitly aligns with NIH rigor and reproducibility expectations. Projects should incorporate robust experimental design, appropriate controls, clear statistical planning, transparent reporting, and replication or independent confirmation where feasible.
Why does the FOA emphasize cross-validation across labs and methods?
Cross-validation is intended to strengthen confidence that observed effects of target modulation are real and generalizable. The FOA expects validation that does not depend on one laboratory or one type of experiment, reducing the likelihood that the field advances targets that fail under more stringent testing.
Are clinical trials allowed under this opportunity?
No. The FOA states "Clinical Trial Not Allowed," keeping the focus on preclinical and mechanistic functional validation work rather than testing interventions in human participants.
What diseases and dementia types are within scope?
The scope is broad across the ADRD landscape. Applications may focus on frontotemporal degeneration (FTD), Lewy body dementias (including dementia with Lewy bodies, DLB), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias, including multiple-etiology dementias (MED) and related diagnostic/biological challenges.
Is the opportunity limited to one subtype of dementia?
No. The FOA is designed to support a pipeline of validated targets across diverse ADRD mechanisms, including neurodegenerative, synucleinopathy-related, tau-related, vascular, and mixed-pathology presentations.
What does "cooperative agreement" imply for award management?
A cooperative agreement typically involves a closer working relationship with NIH than a standard grant. The FOA describes shared oversight, milestone-driven management, and coordination intended to keep the project aligned with functional validation and reproducibility goals.
How important is collaboration in this FOA?
Collaboration is treated as a core feature. Applicants are expected to propose substantial teamwork among independent laboratories, which supports the cross-validation expectation and strengthens confidence in the results.
What is the intended end product of a successful UG3/UH3 project?
The intended outcome is a strong, reproducible functional validation package showing that modulating a human-relevant target changes disease-related biology. This package should justify later translational steps such as lead discovery or preclinical therapeutic development and help the field avoid over-investing in targets that do not hold up under rigorous testing.
Who is eligible to apply?
The eligible applicant pool is broad and includes U.S.-based organizations such as state, county, and local governments; public and private institutions of higher education; federally recognized tribal governments and certain tribal organizations; public housing authorities/Indian housing authorities; nonprofits with or without 501(c)(3) status; for-profit organizations (other than small businesses) as well as small businesses; and other eligible entities.
Are specific institution types encouraged or explicitly listed as eligible?
Yes. The FOA calls out categories often associated with broadening participation, including Historically Black Colleges and Universities (HBCUs), Hispanic-serving institutions, Tribally Controlled Colleges and Universities (TCCUs), Alaska Native and Native Hawaiian Serving Institutions, Asian American Native American Pacific Islander Serving Institutions (AANAPISIs), faith-based or community-based organizations, and U.S. territories or possessions.
Are foreign institutions or non-U.S. entities eligible to apply?
No. Non-U.S. entities and foreign institutions are not eligible to apply under this FOA.
Can a U.S. organization include a non-U.S. (non-domestic) component?
No. The FOA states that non-domestic components of U.S. organizations are not eligible.
Are foreign components (as defined by NIH policy) allowed?
No. The FOA explicitly does not allow foreign components as defined by NIH policy.
What are CFDA numbers associated with this opportunity?
This FOA is listed under CFDA numbers 93.853 and 93.866.
What should a competitive UG3-to-UH3 plan include?
A competitive application would lay out a complete plan across both phases with clear milestones, showing how the team will: (1) build the tools and models needed to perturb the target in disease-relevant systems; (2) measure functional outcomes meaningfully linked to ADRD biology; and (3) replicate and cross-check findings across labs and methods using strong rigor and reproducibility practices.
What kinds of experimental systems are mentioned as relevant to this FOA?
The FOA mentions cellular systems, tissue-based assays, and in vivo disease models as examples of experimental systems that may be developed or improved, alongside protocols and measurement strategies to capture biologically meaningful changes tied to ADRD mechanisms.
What does it mean for a target to be "realistically testable" under UG3?
In the UG3 context, this means demonstrating that the team can build or refine the tools and experimental foundation needed to perturb the target and reliably measure downstream functional consequences in systems that are relevant to ADRD biology.
Why does NIH require a human-data rationale rather than animal-only rationale?
The FOA is designed to prioritize targets that connect back to human disease signals (genetic or tissue expression evidence), aiming to reduce translational risk and focus effort on targets more likely to matter in human ADRDs.
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