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Engineering Next-Generation Human Nervous System Microphysiological Systems

NAMHC Concept Clearance

Presenter:

David M. Panchision, Ph.D.
Division of Neuroscience & Basic Behavioral Science

Goal:

This concept encourages research directed toward developing next-generation human cell-derived microphysiological systems (MPS) and related assays that replicate complex nervous system architectures and physiology with improved fidelity over current capabilities. Supported projects will be expected to enable future studies of complex nervous system development, function, and aging in healthy and disease states.

Rationale:

Human cell-based assays (e.g., using induced pluripotent stem cells) hold promise for identifying molecular, cellular, and circuit defects; identifying novel targets; and developing new therapeutics for patients with complex brain and other nervous system disorders. However, the methods to generate and analyze relevant cells and circuits must be made robust, replicable, and predictive for normal nervous system function as well as pathophysiology. A drawback of reductionist assays like monolayer culture is that they cannot resolve many developmental and aging trajectories, anatomical features and circuit activity representative of in vivo nervous system function.

As an alternative, there are increased efforts to generate assays with more physiologically-relevant organization, including three-dimensional MPS systems such as organoid/spheroid culture, tissue chips, and chimeras. While these assays currently reproduce some important features of in vivo prenatal development, a major unresolved technical hurdle is the application of human cell-based assays to evaluation of circuit maturation, connectivity, and aging, including its relationship to specific circuits involved in disease states. Addressing this complex technical challenge requires the collaboration of experts from diverse fields, including developmental and stem cell biology, circuit and systems level neuroscience, materials science, engineering and bioethics.

Studies of interest could include but are not limited to:

  • Utilization of novel materials, substrates, or synthesis technologies to promote anatomically and physiologically relevant tissue organization and maturation;
  • Integration of defined cell types consistent with relevant nervous system anatomy into functional units (e.g., tripartite synaptic, neurovascular);
  • Novel strategies to faithfully reproduce relevant regional cellular organization with both short- and long-range anatomical connectivity or complex functional features such as neural oscillatory activity or activity-dependent plasticity;
  • Novel strategies for temporally or spatially cell-selective monitoring or manipulation of gene expression, protein function or live cell activities;
  • Comparison with human anatomical, histological, or systems-level data to facilitate assay validation