Abstract

Type 1 Diabetes (T1D) is a chronic metabolic disorder characterized by insulin deficiency due to progressive loss of pancreatic Beta cells. There is no cure for this disease; people living with T1D have to take insulin injections in order to have life-sustaining metabolism. Current statistics (2017-2018) indicate that there are >1 million people living with T1D in the US alone and the rates of T1D are increasing worldwide each year especially in children and adolescents, yet we still do not understand how or why this disease occurs. The prevailing models posit that Beta cell-targeted autoimmunity is the sole driver of the disease. Under this paradigm, Beta cells are simply ‘sitting ducks’ waiting to be destroyed by a dysfunctional immune system. However, it remains poorly understood the extent to which changes in Beta cells themselves may play an active role in triggering or sustaining the autoimmunity. Do Beta cells themselves contribute to their progressive demise? Preliminary results have indicated that Beta cells undergo a form of DNA damage-induced senescence and acquire a proinflammatory secretome prior to T1D onset. Senescence is a form of stable cell cycle arrest in response to cellular damage and involves a variety of other features, which collectively activate the immune system to ensure clearance. In this project, I will test the hypothesis that Beta cell senescence is a novel driver of T1D pathogenesis. I will investigate the role of beta cell senescence as a causal factor in T1D, the molecular basis for senescence-related changes in Beta cells and explore avenues to determine whether elimination of senescent Beta cells can prevent T1D development. Together these studies will furnish new insights into the causes of T1D and suggest novel avenues for preventive therapies.