Interrogation of Dynamic RNA Modifications in Beta Cells in Type 1 Diabetes
Contact PI: Rohit Kulkarni, MD, PhD, Joslin Diabetes Center (UC4 DK116278)
Chuan He, PhD, Investigator, University of Chicago
Start Date: September 20, 2017
End Date: August 31, 2021
The number of people with diabetes worldwide is predicted to increase from 400 million in 2015 to over 600 million in 2040. The health care costs of treating the disease account for >10% of the global health expenditure and continue to be a huge economic burden (IDF World Atlas 2015). Type 1 diabetes mellitus (T1DM) constitutes up to 15% of the disease burden. T1D is an autoimmune disease, believed to be triggered by genetic or environmental factors in early life, and which leads to an antibody-mediated destruction of insulin producing pancreatic β-cells that promotes severe hyperglycemia. In contrast, type 2 diabetes mellitus (T2DM) typically develops late in life and results from insulin resistance in multiple target tissues and inflammation coupled with a poor compensation by the β-cells. The precise mechanisms that trigger the cascade of events ultimately leading to beta cell death are still not fully understood. Several observations have prompted renewed interest in the beta cell itself as a target tissue that could initiate the disease process. In this context the recent identification of RNA methylation as a potential regulatory mechanism that contributes to the ability of a cell to adapt to rapid changes in the environment provides a provocative approach to investigate changes in beta cells that precede the development of the T1D phenotype. We seek to interrogate alterations in the dynamic methylation of RNA, specifically, N6-adenosine methylation (m6A) in beta cells to identify the signatures that might provide important clues to processes that contribute to beta cell death. In this proposal we will focus on: 1) Characterizing the dynamic RNA methylation changes in islet cells obtained from models of type 1 diabetes; and 2) determining the functional relevance of alterations in N6-methyladenosine (m6A) in human islets and β-cells. Finally, we will contrast the RNA methylation changes observed in the islets in the T1D models with proteomics and gene expression signatures in islets obtained from patients with T1D.
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