Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes (T2D). Efforts to quell the development of T2D are essential to prevent subsequent cardiovascular complications. The outlined studies will identify mechanisms underlying pancreatic beta-cell death and hyperglycemia in T2D, which directly exacerbate CVD. Progressive loss of insulin-producing beta-cell mass/function in diabetes augments hyperglycemia and exacerbates beta-cell stress/death in a feedback cycle. Pancreatic islet amyloidosis by the human hormone islet amyloid polypeptide (hIAPP) is an important contributor to loss of beta-cell mass in type 2 diabetes (T2D), but the mechanisms of toxicity are ambiguous. Recent advances in our laboratory have defined the molecular properties of toxic species produced during islet amyloidosis and their interaction with the receptor for advanced glycation end products (RAGE), thereby identifying a new receptor-mediated mechanism of beta-cell death in T2D. However, the intracellular signaling pathways by which RAGE regulates hIAPP-induced beta-cell/islet defects are unknown. The proposed studies will determine how RAGE mediates hIAPP-induced beta-cell/islet toxicity in T2D by testing the hypothesis that extracellular hIAPP/RAGE binding induces intracellular RAGE/DIAPH1 interactions that activate Rho GTPase RAC1 signaling leading to ROS production, inflammation, beta-cell dysfunction and apoptosis. Critical test of this hypothesis will be implemented via two synergistic specific aims using beta-cells, murine islets, mouse models and human islets and pancreatic tissue to: 1) define the role of RAGE/DIAPH1 signaling in hIAPP induced beta-cell/islet toxicity, and determine whether inhibition of RAGE/DIAPH1 signaling mitigates islet amyloidosis induced beta-cell/islet inflammation, dysfunction and apoptosis; and 2) test the hypothesis that RAGE/DIAPH1 signaling is required for islet amyloidosis-induced beta-cell/islet pathology in diabetes. The aims build logically on our recent findings and are well supported by preliminary data. Successful completion of these aims will identify primary targets for therapeutic interventions that block functional damage to beta-cells/islets in T2D and prevent subsequent CVD. They will also provide critical data for submission of a full NIH R01 proposal.
|Program type||Scientist Development Grant|
|Effective start/end date||01/01/2017 → 12/31/2019|