Kennedy, James (2022). The identification of potential repurposed drug compounds and metabolic-altering factors that either inhibit or enhance the process of enclysis. University of Birmingham. M.Sc.
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Kennedy2022MScByRes_Redacted.pdf
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Abstract
Regulatory T cells (Tregs) play a major role in tempering inflammation in the liver and have become a novel tool in the treatment of autoimmunity and cancer. Through recent findings, a brand-new process of live T cell capture has been identified to toggle immunogenicity in the liver. Hepatocytes are able to capture live Treg cells in the hepatic microenvironment and eliminate them in acidic vesicles. This process, termed enclysis, carries huge potential as a therapeutic target against autoimmunity and cancer in the liver. As enclysis is a novel process, it has not yet been exploited therapeutically. In this project, 1200 FDA-approved drug compounds, where mechanism of action is already known, were investigated using high-throughput screens on their ability to modulate the process of enclysis. After three separate screens, using manual quantification of cell-in-cell structures, a shortlist of five inhibitors and five enhancers were identified to have their effect validated in vitro. Possible metabolic intervention was also investigated to determine any involvement of certain metabolites on the process. After in vitro validation, we identified four drug compounds (two inhibitors and two enhancers) as competent modulators of enclysis as well as a variety of metabolic conditions that could aid in inhibiting or enhancing the process. These drug compounds can now carry therapeutic potential in the possible treatment of autoimmunity and cancer in the liver.
| Type of Work: | Thesis (Masters by Research > M.Sc.) | ||||||
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| Award Type: | Masters by Research > M.Sc. | ||||||
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| Licence: | All rights reserved | ||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | ||||||
| School or Department: | Institute of Immunology and Immunotherapy | ||||||
| Funders: | None/not applicable | ||||||
| Subjects: | R Medicine > RM Therapeutics. Pharmacology | ||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/13053 |
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