Type 1 Diabetes is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. While there has been significant progress in understanding immune-mediated beta cell destruction, the role of beta cell dysfunction in the underlying etiology of T1D is less clear. We have discovered that pancreatic beta cells acquire a proinflammatory secretome reminiscent of SASP during T1D in mice and human. SASP beta cells can remodel the islet environment in a paracrine manner by promoting bystander senescence and immune surveillance. We have developed drugs that selectively eliminated SASP beta cells without altering the abundance of the major immune cell types involved in the disease. Significantly, elimination of SASP beta cells halted progression of beta cell destruction and was sufficient to prevent diabetes. In this proposal, we focus on human beta cells and characterize the non-cell autonomous effects of SASP on islet microenvironment and develop drugs that can selectively target human SASP beta cells. We utilize the secretory properties of SASP beta cells to identify biomarkers that can report on the efficacy of drug treatment and progression of the disease.
Recent work from our laboratory has shown that beta cells acquire a proinflammatory secretome reminiscent of SASP during T1D and selective clearing of these cells prevented diabetes. In this proposal, we characterize the non-cell autonomous effects of senescent human beta cells on the islet microenvironment and develop senolytic compounds that can selectively target human SASP beta cells. We propose to identify biomarkers for assessing the efficacy of senolytic treatment and progression of the disease to pioneer new therapeutic approaches for T1D.
