Engineering Next-Generation Human Nervous System Microphysiological Systems (R21 Clinical Trials Not Allowed)

PAR-25-199

The purpose of this Notice of Funding Opportunity (NOFO) is to stimulate basic technology-focused research to develop next-generation human cell-derived MPS and related assays with improved fidelity to complex human brain, spinal cord, and/or sensory end organ circuit physiology, which will ultimately facilitate analysis of higher order functional deficits relevant to complex nervous system diseases. This NOFO is distinct from others that focus on optimization and scalability of assays for compound screening, although projects could, in principle, have utility for late stage evaluation of drug efficacy and toxicity. These models will have a multi-lineage, complex architecture representing the normal characteristics and functions of the relevant nervous system structure (e.g., sensory input systems, brain or spinal integrative systems, motor output systems) and will substantially exceed the state of the art in cellular maturation and integration, allowing reproducible measurement of human-relevant circuit-level activity under physiological conditions over a long period.

This NOFO encourages innovative approaches that are first-in-class, those that propose to substantially exceed the state of the art in tissue organization and function. These can be high risk, high impact designs. Additionally, this NOFO encourages approaches that aim to improve robustness and reproducibility of physiologically relevant circuit or supportive systems-level measures.

All applications should define the current state of technology as a benchmark against which the new assay system(s) will be developed and measured. Example approaches include, but are not limited to:

• Utilization of novel materials, substrates or synthesis technologies (e.g., 3D printing, bioreactors, microfluidic platforms) to promote anatomically and physiologically relevant tissue organization and/or maturation.
• Integration of defined cell types consistent with relevant nervous system anatomy (e.g., excitatory, inhibitory & modulatory neurons, astrocytes, oligodendrocytes, microglia, pericytes, endothelial cells) into functional units (assembloids) that may include multipartite synapses, vascularization-perfusion, blood-brain barrier, glymphatic system and/or cerebrospinal fluid flow.
• Novel strategies to faithfully reproduce relevant regional cellular organization (e.g., dorsoventral, rostrocaudal, laminar, columnar or nuclei structure), with both short- and long-range anatomical connectivity (e.g., local inhibitory-excitatory and/or modulatory connections, projections to distant lamina or nuclei).
• Novel strategies to promote maturation of metabolism, signaling, synaptic activity, and connectivity in the cell-based assay.
• Development of human cell-based assays with complex functional features relevant to complex nervous system disorders and diseases (e.g., intrinsic and/or dynamical network properties of cell assemblies such as neural oscillatory activity, activity-dependent plasticity).
• Inclusion of conditional or intersectional strategies that allow temporally and/or spatially cell-selective monitoring or manipulation of gene expression/function or of live cell activity and function.
• Inclusion of innovative approaches to distinguish or deconvolute heterogeneous cell phenotypes in these assays (e.g., multi-parameter single cell analysis), including those that are minimally perturbing.
• Evaluation of how data obtained from the proposed assay compares with human anatomical, histological or systems-level data, or data from other physiologically relevant paradigms, to facilitate assay validation. Investigators are encouraged to explore data and tools being developed under the NIH BRAIN Initiative, BrainSpan, PsychENCODE and the PsychENCODE Human Brain Development Atlas, Human Connectome Project, AMP-AD, or related efforts which, if utilized, could further the authentication of human brain cell-derived assays.

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

Amanda DiBattista, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-9350
Email: amanda.dibattista@nih.gov