CAREER: Defining the regulators of enteric plasticity in engineered microfluidic environments

Directly studying cells in a living human body remains challenging, so engineers employ small fluidic devices that contain cells, called microphysiological systems, to study how cells behave in healthy and diseased states outside of the body. This Faculty Early Career Development Program (CAREER) award supports research to engineer and apply microphysiological systems to better understand how the nervous system regulates the gut in response to inflammation.

These models have wide applications to other organs in the body and will advance knowledge in neurobiology and engineering for human health discovery. Integrated at each level of this project is education and community outreach components to support diversity in science and engineering through hands-on, in-person, and virtual kit-based workshops, summer internships, as well as collegiate coursework and research, and annual programmatic assessment.

The technical difficulty of examining human neural circuits directly has limited the ability to understand neural communication in health and disease. The millions of enteric neurons innervating the gut, for example, dynamically undergo synaptic management in response to signals from the epithelium lining the gut lumen. How, when, and why peripheral neural plasticity is turned on and off, as well as which signals are transduced from the luminal space remains unknown, in part due to insufficient availability of innervated models.

This Faculty Early Career Development Program (CAREER) award will harness a new in vitro microphysiological system (MPS) that combines human primary enteric neurons and epithelium to systematically examine cell fate, function, and plasticity in response to perturbing the epithelium. Genetic engineering with live microscopy, effluent profiling, pilot transcriptomics, histology, and statistical analysis will give insight and predictions into perturbed cell behavior compared to native tissue and non-perturbed controls to identify master regulators of enteric neural dynamics.

The MPS technology can be applied broadly to other innervated organ systems and the understanding garnered of the plastic behavior of enteric neurons will facilitate the evaluation of the role of the brain-gut-axis in human health, disease progression, and therapeutic discovery.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.