Jagged 1-Notch signaling determines ? cell maturity and function

Summary/Abstract Obesity-induced Type 2 Diabetes (T2DM) continues to increase at an alarming rate resulting in a substantial burden of long-term complications and healthcare costs. T2DM is now the leading cause of end-stage renal disease and one of the leading causes of blindness worldwide, as well as a disproportionate contributor to cardiovascular morbidity and mortality. As such, understanding mechanisms of T2DM pathogenesis is key in tackling the growing prevalence in what some consider the largest epidemic in human history. Although insulin resistance is the hallmark of Type 2 diabetes (T2DM), it manifests as hyperglycemia only in the setting of ? cell insufficiency. Pathophysiologic mechanisms underlying this failure requires further elucidation. We have recently shown that Notch signaling is a novel regulator of ? cell function, and glucose homeostasis. Notch activity is regulated by ligand (Jagged 1/2, and Delta-like 1/3/4) availability. We find that islets isolated from HFD-fed or leptin receptor-deficient db/db mice have increased Jagged1 expression as compared to chow or db/+ controls, without change in other Notch ligands, in parallel to increased Notch activity. These data led us to hypothesize that Jagged1 is both sufficient and necessary to transduce Notch signaling in ? cells and is a potential regulator of ? cell function, maturity and glucose homeostasis (Aim 1 and Aim 2). To investigate this, we generated novel ? cell specific Jagged1 gain-of-function and knock-out mice. By identifying the ligand-receptor interaction, we postulate that we can take advantage of this knowledge for therapeutic benefit. To this end, we have generated dominant negative mutants of the Notch receptor lacking the intracellular Notch domain that specifically block either Jagged or Delta-like ligands. As a translational approach, we will investigate if increased Jagged1 is also seen in islets from patients with and without T2DM (Aim 3). The current data on Notch signaling in ? cells shows promise for furthering the understanding of the pathophysiology in T2DM. In studying this mechanism further, we hope to provide a novel therapeutic strategy in preventing a disease that continues to be a growing concern worldwide. This training plan will develop my skills in understanding determinants of ? cell function and maturity in the setting of hyperglycemia. The proposed study investigating Jagged 1-Notch signaling will be a stepping stone towards my goal of becoming an independent researcher.