Stem Cell Assay Program
This Program supports the optimization and implementation of innovative stem cell-based assays for novel biological readouts and mechanisms relevant to mental disorders. The program is premised on the developmental potency/plasticity and self-organizing capacity of human embryonic stem cell (hESC), induced pluripotent stem cell (hiPSC) and related somatic cell reprogramming derivatives, which can be exploited to enable discovery‐based analysis of the genomic architecture of disease risk, identification of biological mechanisms, and therapeutics discovery for human disease. This technology is particularly significant for the study of tissues, such as brain, that are rarely if ever accessible as biopsies from living patients. The program supports efforts to address the principal challenges in establishing reliability of stem cell-based assays. The first challenge is to reduce variability and increase efficiency and replicability in the protocols not only for generating the cell lines and their derivatives but also to increase the robustness of the assays made from the cells. The second challenge is to obtain assays that meaningfully relate to the mechanisms of pathophysiology and can distinguish important differences in disease phenotype from patient to patient. To address this, key components of the program include support for:  production and dissemination of human donor-derived resources such as hiPSCs;  technology development directed at improving physiological fidelity, technical rigor and scalability of human cell-based assays; and  implementation of assays for biological discovery of disease-relevant developmental mechanisms.
Areas of Emphasis
- Generation of hiPSC lines from human subject biospecimens. As detailed in NOT-MH-21-265 investigators are expected to outline plans for sharing cell lines and derivatives and are strongly encouraged to discuss plans with the Program Officer early in the planning stage and prior to submitting an application.
- Optimizing differentiation protocols to direct hESC/hiPSC or somatic cells to relevant cortical and subcortical cell types suitable for functional genomic or simplified cellular assays; optimizing assays for scalability, durability to processing, reproducibility and experimental signal relative to noise.
- Optimizing next-generation human cell-derived microphysiological systems (MPS) including organoids and tissue chips along with related (e.g., chimera/engraftment) assays to model complex nervous system architectures and physiology with improved fidelity over current capabilities.
- Cross-paradigm comparative studies to explore hiPSC fidelity (e.g., against existing human reference data) and evolutionarily distinct features (e.g., against non-human primate iPSC lines) in order to enhance utility for studying disease mechanisms.
- Implementing hESC/hiPSC-based assays, including those that are derived from human patients or engineered to carry disease-associated genetic variants, in order to characterize disease-relevant developmental mechanisms. Applicants are encouraged to request access to the NIMH Repository and Genomics Resource List of Studies or hiPSC collection to determine if source cells for reprogramming or existing hiPSC lines are already available.
Areas of Lower Priority
- Research premised on ‘candidate’ risk genes that are not identified by well-powered, statistically significant genome-wide association (see NOT-MH-18-035).
- Research premised on ‘candidate’ environmental risk exposures that are not based on well-powered, statistically significant epidemiological data.
Applications should adhere to published recommendations detailed in a notice in the NIH Guide (NOT-MH-14-004) and summarized in Enhancing the Reliability of NIMH-Supported Research through Rigorous Study Design and Reporting on the NIMH website. Applicants are also strongly encouraged to discuss their proposals with the institute contact listed below prior to the submission of their applications to ascertain that their proposed work is aligned with NIMH funding priorities.
David M. Panchision, Ph.D.
6001 Executive Boulevard, Room 7197, MSC 9641