The role of tomosyn-2 in insulin secretion

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DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is reaching epidemic proportions in Western societies. T2D occurs when the ß-cells of the pancreas do not secrete enough insulin to properly regulate peripheral blood glucose levels, usually in the face of obesity and associated peripheral insulin resistance. The mechanisms underlying insulin secretion are not properly understood. Using a forward genetics approach, we have discovered that a single nucleotide polymorphism (SNP) in the protein-coding region of the gene for tomosyn-2 is directly correlated with the hypoinsulinemic/hyperglycemic phenotype. Tomosyn-2 is a relatively uncharacterized protein and the mechanism by which it regulates insulin secretion is not known. The work proposed here in this Pathways to Independence Award application has two primary goals: 1) to elucidate the mechanism by which tomosyn-2 regulates insulin secretion in pancreatic ß-cells, and 2) to use my development of this novel area of T2D research to facilitate the development of my career from the mentored phase to an independent phase. During the mentored phase of the grant, I will receive training in mass spectrometry, in vitro liposome fusion assays, membrane biochemistry, and the generation of the tomosyn-2 knockout mouse. The research conducted in the mentored phase will examine the effect of identified phosphorylation sites on the ability of tomosyn-2 to regulate insulin secretion and to understand the mechanism by which tomosyn-2 is targeted for proteosomal degradation. During the independent phase of the grant, my research will examine the mechanism by which tomosyn-2 inhibits insulin secretion by regulating the activity of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and characterize the role of novel tomosyn-2 binding proteins. These studies will provide novel clues to the mechanism by which tomosyn-2 inhibits insulin secretion and will further our understanding of the regulation of insulin secretio in T2D.