Single Cell Multiomic Analysis of the Human Pancreas in Type 1 Diabetes
- Melton, Rebecca Lynn
- Advisor(s): Gaulton, Kyle J
Abstract
Type 1 diabetes (T1D) is caused by the autoimmune destruction of the insulin producing pancreatic beta cells, leading to lifelong dependence on insulin therapy. By the time T1D is diagnosed nearly 90% of beta cells have been destroyed and identifying dysregulated processes prior to T1D diagnosis is needed to improve our understanding of T1D pathogenesis as well as facilitate early detection and intervention. Autoantibodies (AAB) against islet-specific proteins are often observed in T1D, and single and multiple AAB positivity (AAB+) can be used as biomarkers for stages of T1D progression. As an autoimmune disorder there is a bidirectional miscommunication between pancreatic cells and immune cells. Understanding inter- and intra-cell type signaling within the pancreas is critical in understanding T1D pathogenesis. In this dissertation, we use multimodal single cell profiling using single nuclei RNA sequencing, single nuclei ATAC sequencing, and paired single cell multiomic sequencing to identify gene regulatory changes in specific cell types throughout T1D progression in the pancreas. In chapter 1, we identified changes in abundance, gene expression and regulation changes in pancreatic cell types including beta cells occurring in recently diagnosed individuals as well as prior to T1D diagnosis in non-diabetic T1D AAB+ individuals. In chapter 2, we combined a large, multimodal map of pancreatic cell type gene regulation with a multi-ancestry genetic risk score for T1D risk loci which revealed changes in non-diabetic single AAB+ donors in individuals at high genetic risk for developing T1D. Together these aims provide insight into how cell types in the pancreas are dysregulated during T1D progression that provide new avenues for understanding disease mechanisms and potential areas for therapeutic intervention.