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Title page for ETD etd-02222017-163339


Type of Document Dissertation
Author Huang, Chen
URN etd-02222017-163339
Title Synaptotagmin IV and Myt factors promote β-cell functional maturation and maintenance
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Chin Chiang Committee Chair
David Bader Committee Member
Guoqiang Gu Committee Member
Maureen Gannon Committee Member
Tony Weil Committee Member
Keywords
  • Synaptotagmin IV
  • Myt factors
  • β-cell
  • diabetes
  • mouse
  • development
Date of Defense 2017-02-21
Availability unrestricted
Abstract
Both type I and type II diabetes are related to β-cell defects in the pancreatic islet of Langerhans. Deriving β-cells from stem cells and other mature cell types provides an important cell source for transplantation-based therapy to treat diabetes. Mechanistic studies of β-cell maturation and functional maintenance are crucial in providing novel insights for the generation of glucose-responsive and long-term sustainable β-cells. In this study, I found that two gene/gene families, synaptotagmin IV (Syt4) and Myt factors are essential to promote β-cell maturation and functional maintenance. Mouse studies provided evidence that Syt4 modulates insulin Ca2+ vesicle sensitivity to facilitate β-cell maturation the neonatal stage. Loss of Syt4 in mice resulted in Ca2+ hypersensitivity of insulin vesicles in β-cells and compromised glucose-stimulated insulin secretion. Conversely, Syt4 overexpression reduced insulin Ca2+ vesicle sensitivity and established the mature insulin secretion profile in the newborn β-cells. Moreover, Myt factors are essential to generate functional β-cells. Postnatal β-cells in a Myt knockout mouse model were characterized by functional failure, cell apoptosis and loss of mature β-cell identity. Loss of Myt factors in β-cells disrupted the expression of genes involved in insulin secretion, β-cell survival and identity maintenance. These combined results suggest that Syt4 and Myt factors can be exploited as molecular targets to promote β-cell maturity and long-term functional maintenance for better clinical β-cell regeneration.
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