Cellular and Molecular Biology of Complex Brain Disorders (R21 Clinical Trial Not Allowed)

PAR-25-037

This NOFO encourages research on the biology of high confidence risk factors associated with complex brain disorders, with a focus on the intracellular, transcellular and circuit substrates of neural function. For the purposes of this NOFO, the term “complex” can refer to a multifactorial contribution to risk (e.g., polygenic and/or environmental) and/or highly distributed functional features of the brain disorder. Studies may be either hypothesis-generating (unbiased discovery) or hypothesis-testing in design and may utilize in vivo, in situ or in vitro experimental paradigms, e.g., model organisms or human cell-based assays. While behavioral paradigms and outcome measures can be incorporated into the research design to facilitate the characterization of intracellular, transcellular and circuit mechanisms, these are neither required nor expected. Studies should not attempt to “model” disorders but instead should aim to elucidate the neurobiological impact of individual or combined risk factor(s), such as the affected molecular and cellular components and their relationships within defined biological process(es). This can include the fundamental biology of these factors, components and processes. The resulting paradigms, component pathways and biological processes should be disseminated with sufficient detail to enrich common and/or federated data resources (e.g., those contributing to the Gene Ontology, Synaptic Gene Ontology, FAIR Data Informatics) in order to bridge the gap between disease risk factors, biological mechanism and therapeutic target identification. See Section IV, Application and Submission Information,   Resource Sharing Plan.

Applicants are strongly encouraged to take advantage of novel technologies (e.g., from the BRAIN Initiative) and other resources (e.g., genetically modified organism repositories, human cell lines from the NIMH Repository and Genomics Resource) that will facilitate the consideration of genetic background / strain differences, sex as a biological variable, sample size and other aspects of experimental/statistical rigor.

Examples of relevant research include, but are not limited to:

• Analysis of gene(s) where variants have been associated with disease risk at genome-wide significance, but where the basic biology of those genes is poorly understood (e.g., where functional analysis would enrich gene ontology). Applicants are encouraged to incorporate state of the art methods for testing the functional effects of genes and gene variants (e.g., CRISPR/Cas9-mediated editing or newly emerging temporal / spatial control technologies).
• Investigations of mechanisms by which high confidence environmental risk factors influence molecular, cellular or circuit-level processes, alone or by interaction with genetic risk factors.
• Incorporation of the developmental trajectory of biological processes into experimental designs, including designs that identify developmentally critical / sensitive periods to environmental influence.
• Optimization and implementation of novel cell-based experimental systems such as induced pluripotent stem (iPS) cells, including those that are derived from human patients or engineered to carry disease-associated genetic variants, in order to characterize disease-relevant mechanisms. Applicants are encouraged to request access to the NIMH Repository and Genomics Resource List of Studies or iPS cell collection to determine if source cells for reprogramming or existing iPS cell lines are already available. Applicants proposing to derive new iPS cell lines should refer to instructions in Section IV. Application and Submission Information, Resource Sharing Plan.
• Development/optimization of new biological tools or scalable technologies for reporting or manipulating the activity levels and neurobiological functions of brain signaling / effector molecules relevant to complex brain disorders.
• Inclusion of computational approaches, which may include mapping of experimentally produced data to existing reference data to inform biological or pathophysiological relevance of results.

The combined budget for direct costs for the two-year project period may not exceed $275,000. No more than $200,000 may be requested in any single year.

Not Required

February 16, 2025; June 16, 2025; October 16, 2025

David Panchision, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-402-3969
Email: panchisiond@mail.nih.gov