Wednesday, April 2, 2025
4/2/2025
Characterizing the Role of Autophagy in Type 1 Diabetes Development - PROJECT SUMMARY/ABSTRACT Type 1 Diabetes (T1D) develops following autoimmune-mediated destruction of pancreatic β-cells and is caused by a combination of genetic and environmental factors. However, the mechanisms that lead to autoimmune targeting of the β-cell remain incompletely understood. One potential contributing factor is defective β-cell autophagy. The autophagy pathway scavenges and degrades cellular proteins and organelles under conditions of stress. Recently, our lab discovered that the pathway of autophagy is impaired in β-cells before clinical onset of T1D. Based on this discovery, and other preliminary results, I hypothesize that dysfunctional β-cell autophagy contributes to autoimmune targeting of β-cells by altering protein degradation and antigen production leading to a change in β-cell–immune cell dialogue. Experiments in aim 1 will assess how β-cell specific deletion of an essential autophagy enzyme (ATG7) in mice affects β-cell survival, stress response, immune cell recruitment/activation, and neoantigen formation. In aim 2, experiments will determine how disrupted autophagy alters β-cell peptide processing and islet immunogenicity. Completion of these aims will determine how impaired β-cell autophagy alters β-cell health/survival, as well as pathways of protein degradation and antigenic peptide formation. These results will help determine whether the autophagy pathway is a useful therapeutic target to modulate disease course. This project and opportunity for fellowship training will also serve as an important launch point for my future career as a physician-scientist. The methods learned and applied to answer these questions will cultivate a diverse skillset of biochemical and molecular biology techniques to apply in future translational focused research. Furthermore, my expanding knowledge on mechanisms of β-cell stress pathways, β-cell autoimmunity, and disease development will help prepare me to become a successful contributor in the field of diabetes research and pediatric endocrinology clinical care. This F30 award entails a 4-year training plan designed to achieve 4 main objectives: 1) develop technical skills and knowledge of important concepts in diabetes research, 2) train in the use and handling of mouse models, 3) enhance written and oral scientific communication, and 4) integrate clinical development with research training. In addition, the collaborative research environment provided by the Center for Diabetes and Metabolic Diseases at the Indiana University School of Medicine (IUSM), and the integrated clinical and research training received in the IUSM Medical Scientist Training Program, will provide an excellent training environment. Also, an advisory committee consisting of a diverse team of carefully selected and well-established investigators, along with a supportive research environment in the laboratory, will further support and aid achievement of the proposed goals.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).