Project 1. The role of Tomosyn family of proteins in regulating insulin secretion and glucose homeostasis.
We positionally cloned Tomosyn-2 under a fasting glucose quantitative trait locus and demonstrated that genetic alterations in the Tomosyn-2 gene increase susceptibility to type 2 diabetes. We also showed that Tomosyn-2 is among the few known endogenous inhibitor of insulin secretion that functions by decreasing the ability of insulin granules to fuse to the plasma membrane. Our data show that Tomosyn-2 acts as a major hub in beta-cells that integrates the nutritional and genetic cues to modulate the proximal steps in the fusion of the insulin granules to the plasma membrane affecting insulin secretion. Currently, we are investigating the molecular mechanism by which Tomosyn-2 inhibits insulin secretion and glucose tolerance in healthy and pathophysiological states. Additionally, we are also investigating the essential role of a similar protein, Tomosyn-1 in insulin secretion, and type 2 diabetes. Using biochemical and cell biology-based approaches in primary cells and knockout mouse models, our laboratory is understanding the role of Tomosyn proteins in regulating whole-body glucose metabolism in lean and obese.
Project 2. The role of secreted proteins complement-1q like (C1ql) (1-4) and G-protein coupled receptors brain adhesion angiogenesis inhibitor (BAI) signaling pathway in insulin secretion.
We discovered a novel C1ql3 secreted protein signaling pathway that specifically inhibits cyclic adenosine monophosphate-stimulated insulin secretion from pancreatic beta-cells. We showed that C1ql3’s adhesion G-protein coupled receptor, BAI3, mediates the inhibitory effects of C1ql3 on insulin secretion. Our laboratory is now interested in understanding the role of this yet-undescribed C1ql3-BAI3 signaling pathway in beta-cells function. Additionally, we seek to understand the role of C1ql and BAI family of proteins in type 2 diabetes.
Project 3. Identification and characterization of novel secreted protein regulators of obesity, age, and genetics that affect the function of key metabolic tissues.
Our lab is interested in developing a methodology to screen for secreted proteins in the tissue of origin and determine their function in the target tissue. For this, we combine the use of gene/protein expression profiling with the coexpression network-based approaches to identify secreted protein regulators and determine their tissue-specific function. Overall, this methodology serves as a ‘hypothesis-generating’ platform for inter-tissue regulators. We have applied this approach to identify a novel C1ql3 signaling pathway affecting beta-cell function and continue to use this approach to find novel regulators of islet function with therapeutic potential.