Saturday, April 20, 2024
4/20/2024
Project Summary The training strategy demonstrated in this document will help me advance my career to be an independent research scientist in the field of diabetes. I propose to assess the role of arginine transport in the regulation of pancreatic islet cell proliferation and hormone secretion. Disease progression of diabetes is attributed to the inability of pancreatic ß-cells to sufficiently secrete insulin and the combined failure to suppress pancreatic a-cell secretion of glucagon. Inhibition of glucagon signaling reduces hyperglycemia for individuals with diabetes.3 However, impairment of glucagon signaling leads to hyperglucagonemia, hyperaminoacidemia, and a-cell proliferation.4,5 Our lab has identified a liver-a-cell axis that contributes to a-cell proliferation through the accumulation of amino acids in the blood.4 We have identified two major amino acids that contribute to a-cell proliferation, glutamine4 and arginine (unpublished data). However, the mechanisms underlying arginine transport in the a-cell specifically and its contribution to a-cell proliferation and secretion are not well defined. The cationic amino acid transporter SLC7A2 is highly expressed in mouse and human pancreatic a-cells. Therefore, we hypothesize that hyperaminoacidemia that results from interrupted glucagon signaling contributes to increased arginine transport promoting a-cell proliferation and dysfunction. Our preliminary studies show that SLC7A2 is required for a-cell proliferation and glucagon secretion even when challenged with strong membrane depolarizing agents challenging current cation-centric models of arginine stimulated secretion (Figure 2 and 4). Using a new a-cell specific Slc7a2 knockout mouse model, we will unravel the molecular mechanisms that lead to arginine-stimulated a-cell proliferation and glucagon secretion. To assess whether SLC7A2 in a-cells is necessary for amino acid-dependent a-cell proliferation, Slc7a2 knockout in immortalized mouse aTC1-6 cells and an inducible a-cell specific Slc7a2 knockout mouse model will be used to assess changes in a-cell proliferation and mass. Additionally, the mechanism of arginine-induced mTORC1 activation will be targeted to determine if arginine activates mTORC1 through the inactivation of the CASTOR1- GATOR2 pathway (Aim 1). Furthermore, to test the ability for arginine transport via SLC7A2 to modulate glucagon secretion we will combine tools used in Aim 1 with chemical and genetically encoded Ca2+ sensors to observe changes in a-cell glucagon secretion. We will also measure nitric oxide levels, and test the affect of nitric oxide on glucagon secretion to understand the mechanism behind arginine-induced glucagon secretion (Aim 2). Successfully accomplishing this study will enhance our current understanding of amino acid-induced a- cell proliferation and function, as well as broaden the possibilities of therapeutic treatments for diabetes. My training will be achieved through the execution of this study utilizing the fantastic resources and facilities provided by Vanderbilt and thorough mentorship from my highly qualified mentors, Drs. Danielle Dean and David Jacobsen.
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