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MEMP - Thesis Defense - Benjamin E. Mead

Thursday, May 3, 2018

MIT E25-119

Building a Paneth Cell: Exploring Cellular Origin and Function to Inform Intestinal Host-Microbe Interaction and Disease

Understanding how our bodies interact with our resident gut microbes may unlock new therapies for multiple diseases. However, we presently lack representative models to study such interactions, limiting therapeutic development.Here, we advance methods of cellular bioengineering to create high-fidelity models of intestinal cell types, in particular the microbe-interfacing antimicrobial Paneth cell. With this model, we study at scale molecular interventions that direct Paneth cell development and function as a means to modulate our gut microbes in health and disease.

We first present a generalizable approach using single-cell RNA sequencing to compare the identity of in vivoPaneth cells to those of in vitroorganoids and based on lineage-defining differences between the two, nominate small molecule interventions to improve model representation.We then validate our improved Paneth cell model through rigorous characterization and a demonstration of functional (antimicrobial activity, niche support) improvements in Paneth cell physiology following our intervention.

With this high-fidelity Paneth cell model, we built a scalable platform to study interventions which may enhance cell function and development. As a proof-of-concept screen, we use a well-defined and clinically-relevant set of small molecules to identify drugs that enhance Paneth cell differentiation and antimicrobial function. We validate the most potent drugs with additional analyses, revealing multiple molecular targets that may serve as therapeutic candidates to restore Paneth cells in disease or act as a new approach to therapeutically shape the gut microbiota.

Thesis Supervisor:
Jeffrey M. Karp, PhD
Professor of Medicine, BWH, HMS

Thesis Committee Chair:
James J. Collins, PhD
Termeer Professor of Medical Engineering and Science, MIT

Thesis Readers:
Scott B. Snapper, MD, PhD
Director, IBD Center, Professor of Medicine, BCH, HMS

Alex K. Shalek, PhD
Pfizer-Laubach Career Development Assistant Professor, MIT

Date and Time: 
Thursday, May 3, 2018 - 3:00pm to 5:00pm

MIT E25-119