The ASPIRE Path in Molecular Medicine

Type 1 diabetes is a prototypical example of an organ specific autoimmune disease. During the progression of disease in susceptible individuals, T and B lymphocytes become activated to destroy insulin-producing beta cells; meanwhile, these same highly aggressive effector lymphocytes leave other cells of the pancreas untouched. Interestingly, most healthy individuals also possess autoreactive lymphocytes; however, in these individuals, these cells never become activated to destroy their target tissue.

Since insulin and other hormone antigens are ubiquitously present in the circulation, autoreactive cells in all individuals will encounter them; therefore, tolerance to these antigens must be maintained by differences in the cellular response to antigen encounter. The activation of cellular effector programs requires coupling of this antigen encounter to signal transduction events that lead to the evolution of effector function. The central hypothesis of my dissertation project is that the intracellular signaling events coupling the antigen receptor to an effector response are differentially regulated in the autoimmune as compared to the protected settings. To investigate this hypothesis, I will study B and T cell receptor signaling in mouse models of Type 1 diabetes, in models of islet transplantation tolerance and rejection, and in human subject samples from patients with Type 1 diabetes. Presently, my project is developing new technologies to study the activation and regulation of these signaling processes in single cells by developing a mass cytometry (CyTOF) approach to this analysis coupled with training in bioinformatics and systems biology analysis.

My clinical mentor Dr. Bill Russell is a pediatric endocrinologist, director of the Director of the Children’s Diabetes Program and The Division of Endocrinology and Diabetes at Vanderbilt. My time in clinic will allow me to understand the presentation, diagnosis and treatment of autoimmune diabetes. Understanding the genetic heterogeneity and variability of diabetes disease progression will allow me to gain an understanding of the challenges to finding a cure to this awful disease. Overall, we anticipate that these studies will lead to 1) the identification of novel lymphocyte subsets involved in autoimmunity and defined by altered intracellular signaling; 2) the discovery of new druggable targets for diabetes prevention and reversal; and 3) an enhanced ability to identify persons at risk for autoimmunity based on the lymphocyte functional signature that my project will develop.