Inhibiting Smad2 Signaling in Adult Hyperglycemic Mice Enhances β-Cell Resilience
Madison Thomas - Final Dissertation Defense - HUGEN PhD Candidate
Department of Human Genetics Doctoral Candidate, Madison Thomas, will defend the following dissertation on “Inhibiting Smad2 Signaling in Adult Hyperglycemic Mice Enhances β-Cell Resilience”
COMMITTEE CHAIR: George K, Gittes, MD
Committee Members:
F. Yesim Demirci, MDKrishna Prasadan, PhDBeth L. Roman, PhD
ABSTRACT:
Type 2 diabetes (T2D) is a common chronic metabolic syndrome clinically characterized by dysregulation of blood glucose levels. Current treatments for T2D alleviate the symptoms of hyperglycemia but do not treat the underlying mechanism of β-cell failure. Transforming growth factor-beta (TGFB) signaling is essential in orchestrating the expansion, growth, and function of mouse pancreatic β-cells. TGFB signaling is a broad pathway, but it can be modified with precision by manipulating downstream SMAD2 signaling. This dissertation examined inhibition of Smad2 as a target for improving diet-induced hyperglycemia in mice, with the translational goal of an rAAV-mediated gene therapy for T2D.
First, I used a tamoxifen-inducible β-cell-specific mouse model (Smad2βKO) to suppress Smad2 mRNA in the β-cells of adult mice after hyperglycemia was established. Smad2βKO improved glucose physiology in vivo and islet function ex vivo. Next, I defined the mechanism behind this recovery. The rescue was distal. Smad2βKO β-cells recovered their mature identity, proliferated and expanded total β-cell volume, and had more mature insulin granules and a larger readily releasable pool, while glucose sensing and calcium handling were unchanged. These islets also showed a trend toward reduced ER stress and mitochondrial biogenesis. Improved glycemic control reduced hepatic lipid accumulation, suggesting systemic improvement in glucose handling. Last, I attempted to translate Smad2βKO into a therapeutic intervention in adult hyperglycemic mice using rAAV gene therapy. Cells transduced with AAV-shSmad2 showed efficient knockdown of Smad2 mRNA; however, transduction was not sufficient to produce biological changes. Despite optimization of AAV capsid serotypes and viral titers, the maximum average β-cell transduction achieved in this thesis was about 15%, similar to other reports of rAAV-mediated β-cell transduction.
Inhibition of Smad2 signaling is an attractive target for treating the underlying etiology of T2D, as it improves β-cell function and proliferation. rAAV-mediated infection and transduction of pancreatic β-cells remain a barrier to therapeutic translation in the field of islet biology.
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