Wednesday, December 4, 2024
12/4/2024
Project Summary Type 1 Diabetes (T1D) is a disease indicated by autoimmune-mediated destruction of the pancreatic β-cells in the islets of Langerhans, which form 2-5% of the pancreas. Although the vast majority of T1D research has focused on structural and functional changes in the islets, substantial abnormalities in the exocrine pancreas also occur with this disease. Acinar cells in the exocrine pancreas synthesize, store, and secrete digestive enzymes into the duodenum. The long-term goal of this research is to understand the role of exocrine pancreas dysregulation in the pathophysiology of T1D. This proposal specifically will define changes in central carbon and lipid metabolism in the exocrine pancreas in T1D. I hypothesize that the T1D exocrine pancreas experiences increased TCA cycle turnover and de novo lipogenesis (DNL). I will test this hypothesis through two specific aims. Aim 1 will quantify changes in exocrine pancreatic central carbon metabolism in a transgenic mouse model of T1D. Aim 2 will determine rates of lipid turnover in the exocrine pancreas. The experiments outlined in Aims 1 and 2 utilize a novel pancreas perfusion method to examine exocrine pancreas metabolism. In aim 1 this is combined with nuclear magnetic resonance (NMR) spectroscopy using hyperpolarized substrates as well as gas chromatography-mass spectrometry (GC-MS) to establish the significance of TCA cycle and glycolytic flux in the exocrine pancreas in T1D pathogenesis. Aim 2 utilizes ex vivo, in vivo, and commercially available assays to investigate flux through lipid metabolic pathways and lipid storage. This research plan addresses the unmet biomedical need to understand acinar cell central carbon and lipid metabolism, thus provides critical insight on mechanisms that drive exocrine dysfunction in T1D. The knowledge gained through this work will serve as a foundation for understanding how exocrine pancreas dysregulation may affect T1D development and subsequent β-cell dysfunction. The fellowship training plan outlines three goals to accomplish my ultimate career goal of becoming an independent investigator at a tier 1 research institution: i) increase technical expertise ii) improving scientific communication and iii) engaging in mentorship. This proposal encompasses technical training in pancreas physiology, stable isotope tracing, NMR spectroscopy, GC-MS, and metabolomics analysis. The Merritt research group, the Advanced Magnetic Resonance and Spectroscopy (AMRIS) facility, and the Diabetes Institute at the University of Florida provide an exceptional environment in which to acquire these skills. Furthermore, the Merritt laboratory supports the improvement of my scientific communication and mentoring abilities. Ultimately, this training environment is ideal to engage in career development and complete the proposed research.
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