Role of endoplasmic reticulum calcium in beta cell mitochondrial dysfunction, senescence, and onset of type 1 diabetes - PROJECT SUMMARY / ABSTRACT Type 1 diabetes (T1D) is characterized by autoimmune-mediated destruction of the insulin producing β cells of the pancreas causing severe hyperglycemia. Recent evidence suggests that the β cell itself plays a complex role in T1D pathogenesis through activation of cellular senescence, which is associated with secretion of chemokines and proinflammatory cytokines (SASP) that may act to amplify recruitment of immune cells, making the β cells more vulnerable to immune attack. While senescence has been linked with mitochondrial dysfunction in other cell types, the molecular pathways leading to β cell senescence and SASP are largely unknown, leaving a critical need to determine underlying mechanisms to propel the development of novel T1D prevention therapeutics. Calcium (Ca2+) plays a vital role in β cell function, regulating key steps involved in the production and secretion of insulin. The fidelity of these tasks depends on the maintenance of Ca2+ stores, organized at both the cellular and organelle level. The endoplasmic reticulum (ER) serves as a dominant intracellular Ca2+ store, and ER Ca2+ is maintained through activity of the sarco-endoplasmic reticulum Ca2+ ATPase 2b (SERCA2) pump. We have shown previously that β cell SERCA2 expression is reduced in models of T1D, leading to diminished insulin secretion, ER stress, and increased β cell death. My preliminary data has extended these observations and linked loss of SERCA2 activity with decreased mitochondrial function and increased expression of key senescence markers. Against this background, I hypothesize that loss of ER Ca2+ via reduced SERCA2, accelerates β cell senescence and SASP via mitochondrial dysfunction driving the development of T1D. I will test this hypothesis through two specific aims. In Aim 1, I will elucidate the role of ER Ca2+ loss on islet β cell senescence, SASP, and mitochondrial function. In Aim 2, I will define whether SERCA2 activation and/or senolytic treatments, which eliminate senescent cells, can attenuate T1D onset, β cell mitochondrial dysfunction, senescence, and SASP. Completion of this project has the potential to define a novel regulatory role for β cell ER Ca2+ and mitochondrial health during the development of T1D and may inform new paradigms of T1D prevention. With this F31 Predoctoral Fellowship, I will be empowered to complete my research strategy, while also focusing on my training plan, which includes 4 main objectives: 1) Build a detailed and foundational understanding of techniques and concepts in diabetes research, 2) Build strong technical skills in live cell imaging and single cell RNA sequencing analysis, 3) Develop and cultivate mentoring skills, and 4) Enhance my critical thinking skills through written and oral scientific communication. My training plan will be supported by the experienced faculty and collaborative research environment provided by the Center for Diabetes and Metabolic Diseases and Herman B. Wells Center at the Indiana University School of Medicine. In summary, this comprehensive research strategy and training plan will set me on a trajectory to make a lasting impact in the field of T1D research.
