Roles of autophagy and transcription factor EB (TFEB) in β-cell viability and function
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Zou, Yuanjie
issued: 2025-01-07T16:40:35Z
issued: 2024
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Diabetes affects more than 500 million people worldwide and results in serious health complications that contribute to millions of deaths annually. Diabetes is characterized by high blood glucose levels resulting from insufficient insulin production due to dysfunction and loss of insulin-producing pancreatic β-cells. The success of islet transplantation as a functional cure for autoimmune type 1 diabetes is also hindered by dysfunction and death of transplanted β-cells. Autophagy is a conserved cellular process that helps maintain cell function and survival by lysosomal degradation and recycling of damaged cellular components under stress. However, the role of autophagy in β-cell survival under hypoxia and following islet transplantation remains unclear. Furthermore, recent evidence suggests that failure of β-cell autophagy may contribute to β-cell dysfunction and the development of both type 1 and type 2 diabetes, but the underlying mechanisms are not understood. This dissertation investigates the importance of autophagy and lysosomal homeostasis in pancreatic β-cells under diabetes- and transplantation-relevant stress. We created a mouse model with β-cell-specific deletion of the autophagy-related gene Atg5 and demonstrated that basal autophagy is essential for maintaining glucose tolerance and β-cell survival. We further found that autophagy protects β-cells under hypoxic stress and during islet transplantation, as loss of autophagy exacerbated β-cell death and islet graft failure. Prolonged hypoxia was found to impair autophagic flux, and this was associated with lysosomal dysfunction and decreased β-cell levels of Tfeb, a transcriptional master regulator of lysosomes and autophagy. By pharmacologically activating Tfeb, we were able to restore lysosomal function and improve β-cell viability under stress. To further understand the role of Tfeb in β-cells, we generated a β-cell-specific Tfeb knockout mouse. Loss of β-cell Tfeb made the mice more susceptible to str…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/90065
note: ROLES OF AUTOPHAGY AND TRANSCRIPTION FACTOR EB (TFEB) IN β-CELL VIABILITY AND FUNCTION by Yuanjie Zou B.Sc., University of Science and Technology of China, 2012 M.Sc., Dalhousie University, 2015 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Cell and Developmental Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2024 © Yuanjie Zou, 2024 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Roles of Autophagy and Transcription Factor EB (TFEB) in β-Cell Viability and Function submitted by Yuanjie Zou in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Cell and Developmental Biology Examining Committee: Dr. Dan S. Luciani, Associate Professor, Surgery, UBC Supervisor Dr. Francis C. Lynn, Associate Professor, Surgery, UBC Supervisory Committee Member Dr. Brian Rodrigues, Professor, Pharmaceutical Sciences, UBC University Examiner Dr. James D. Johnson, Professor, Cellular & Physiological Sciences, UBC University Examiner Additional Supervisory Committee Members: Dr. C. Bruce Verchere, Professor, Pathology and Laboratory Medicine, UBC Supervisory Committee Member Dr. Elizabeth Conibear, Professor, Medical Genetics, UBC Supervisory Committee Member Dr. Sharon M. Gorski, Professor, Molecular Biology & Biochemistry, Simon Fraser University Supervisory Committee Member iii Abstract Diabetes affects more than 500 million people worldwide and results in serious health complications that contribute to millions of deaths annually. Diabetes is characterized by high blood glucose levels resulting from insufficient insulin production due to dysfunction and loss of insulin-producing pancreatic β-cells. The success of islet transplantation as a functional cure for autoimmune type 1 diabetes is also hindered by dysfunctio…
has type: Thesis/Dissertation
date issued: 2025-05
is shown at: 10.14288/1.0447697
language: eng
degree discipline: Cell and Developmental Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Luciani, Dan S.
type: Text
identifier URI: http://hdl.handle.net/2429/90065