Project Abstracts - CBDS

Chuan He, PhD, Investigator, University of Chicago

Start Date: September 20, 2017
End Date: August 31, 2021

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Abstract

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.

 

Publications

• Redox regulation of m(6)A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes
• m 6 A mRNA Methylation Regulates Early Pancreatic β-Cell Differentiation
• m (6) A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis
• Redox Regulation of m (6) A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes
• Using single-nucleus RNA-sequencing to interrogate transcriptomic profiles of archived human pancreatic islets
• Defective insulin receptor signaling in hPSCs skews pluripotency and negatively perturbs neural differentiation
• RADAR: differential analysis of MeRIP-seq data with a random effect model
• Omics” and “epi-omics” underlying the β-cell adaptation to insulin resistance
• m6A mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes
• How, When, and Where Do Human β-Cells Regenerate?