MEMP PhD Thesis Defense: Madelyn MacRobbie

Detecting Tight Junction-Mediated Epithelial Barrier Dysfunction in Altered Gravity Environments

Cell and tissue mechanisms are influenced by changes in gravity. In astronauts, this can impact health during space missions. One such change is the disruption of epithelial barrier function in space; the epithelium lines body cavities and serves a critical barrier function that prevents things like bacteria from crossing into the body. The barrier’s permeability is regulated by protein complexes called tight junctions, which have been shown to break down in microgravity with results indicating that the spaceflight environment puts astronauts at increased risk of immune dysfunction particularly in long-duration missions. Up to 60% of medical conditions that have been reported in space could correspond to changes in tight junctions. Therefore, there is an unmet clinical need to monitor progression towards tight junction-mediated epithelial barrier dysfunction in space, to implement timely and effective countermeasures before symptom presentation that is detrimental to mission success. 

This thesis targets development of a single point-of-care device that can be used regularly by astronauts in space to monitor for changes in epithelial barrier function. In order to accomplish this, we first seek to identify whether the epithelial responses to external stimuli are correlated across tissue types under Earth conditions. Then, the tissue response to microgravity is investigated. Tissues excised from adult WT mice (SA1: n=8; SA2: n=7) were evaluated in an Ussing chamber with the addition of chemical modulators. The Ussing chamber is the gold-standard method to measure tissue integrity, where electrophysiological properties of a tissue indicates the barrier’s performance. AT-1001 and AT-1002 were applied to tissue in the Ussing chamber as chemical modulators known to target the tight junction protein ZO-1, with the resulting change in barrier permeability measured. Results of SA1 establish that tight junctions respond similarly across epithelial tissue types, establishing the viability of using a proxy location for monitoring the epithelial barrier integrity of the high-risk intestine. SA2 used similar techniques for analysis following exposure to either normogravity or simulated microgravity via a clinostat, which uses two-axis rotation to create a net microgravity force at the center of rotation. Results of SA2 probe the impacts of microgravity on tight junction physiology and demonstrate the systemic nature of the microgravity response. Specifically, SA2 demonstrates that de-localization of the tight junction protein ZO-1 corresponds to functional changes in barrier permeability following microgravity exposure.

These results inform development of a medical device that is capable of measuring changes in the epithelial state. This device is then tested for operation in simulated microgravity in SA3, reaching a technology readiness level of 6. Finally, a path to flight is proposed to enable rapid integration of this device into the spaceflight medical system in SA4.

Thesis Supervisor:
Guillermo Tearney, MD, Ph.D.
Remondi Family Endowed MGH Research Institute Chair
Professor of Pathology, Harvard Medical School

Thesis Committee Chair:
Joseph A. Paradiso, Ph.D.
Director, MIT Media Lab Responsive Environments Group
Alexander W. Dreyfoos Professor, Program in Media Arts and Sciences, MIT

Thesis Readers:
Alessio Fasano, MD
Mass General for Children Vice Chair of Research, Mass General Research Institute
Director, MGH Mucosal Immunology and Biology Research Center
Professor of Pediatrics and Nutrition, Harvard Medical School

Aleksandra Stankovic, Ph.D.
Executive Director, MGH Center for Space Medicine Research
Assistant Professor, Department of Psychiatry, Harvard Medical School

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Topic: Madelyn MacRobbie MEMP PhD Thesis Defense
Time: Wednesday, September 24, 2025, 9:00 AM Eastern Time (US and Canada)

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