Interrogation of dynamic RNA modifications in beta cells in type 1 diabetes

1 型糖尿病 β 细胞动态 RNA 修饰的研究

基本信息

批准号：
9459617
负责人：
CHUAN HE
金额：
$ 192.59万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9459617
关键词：
Adenosine Affect Alpha Cell Antibodies Antigens Apoptosis Area Atlases Autoimmune Diseases Autoimmune Process Autoimmunity B cell repertoire Beta Cell Biological Biological Preservation Brain Cell Death Cell Differentiation process Cell Line Cell model Cell physiology Cells Cellular biology Chemicals Clinical Research Communities Cost Savings Coupled Data Defect Development Diabetes Mellitus Diabetic mouse Disease Economic Burden Environment Environmental Risk Factor Epitopes Eukaryota Event Female Financial compensation Functional disorder Gene Expression Profile Genetic Genetic Translation Goals Health Care Costs Health Expenditures Human Hyperglycemia Immune Inbred NOD Mice Infiltration Inflammation Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Interferon-alpha Islet Cell Islets of Langerhans Lead Life Malignant Neoplasms Mammalian Cell Measures Mediating Messenger RNA Methylation Methyltransferase Modeling Modification Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Phenotype Play Post-Transcriptional Regulation Predisposition Process Proteins Proteomics RNA RNA Splicing RNA methylation Reader Regulation Reporting Research Research Personnel Resources Role Signal Transduction Site Stress Structure of beta Cell of islet TLR2 gene TLR3 gene Testing Time Tissues Transcript Untranslated RNA biological adaptation to stress burden of illness diabetic early childhood global health insight interest islet knock-down mRNA Stability novel protein B

项目摘要

PROJECT SUMMARY The number of people with diabetes worldwide is predicted to increase from 415 million in 2015 to 642 million in 2040. The health care costs of treating the disease account for 12% of the global health expenditure and continue to be a huge economic burden (IDF World Atlas 2015). Type 1 diabetes mellitus (T1DM) constitutes 10-15% of the disease burden and is an autoimmune disease, thought to be triggered by genetic or environmental factors in early childhood, which results in antibody-mediated destruction of insulin producing pancreatic β-cells causing life-threatening hyperglycemia. In contrast, type 2 diabetes mellitus (T2DM) develops later in life and results from insulin resistance in target tissues and inflammation coupled with an inadequate 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 type 1 diabetes 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: 1). Characterize the dynamic RNA methylation changes in islet cells obtained from models of type 1 diabetes; 2) determine the functional relevance of alterations in N6-methyladenosine (m6A) in human islets and β-cells; and 3) explore changes in additional methyl marks in RNA in islet cells from models of T1D mouse model. 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.

项目概要全球糖尿病患者人数预计将从 2015 年的 4.15 亿增加到 6.42 亿到2040年，治疗该疾病的医疗费用将占全球卫生支出的12% 1 型糖尿病 (T1DM) 仍然是巨大的经济负担（IDF 世界地图集 2015）。 10-15% 的疾病负担，是一种自身免疫性疾病，被认为是由遗传或儿童早期的环境因素，导致抗体介导的胰岛素产生破坏相比之下，胰腺β细胞会导致危及生命的高血糖。它是在生命后期发展的，是由靶组织中的胰岛素抵抗和炎症加上 β细胞补偿不足。触发一系列事件最终导致 β 细胞死亡的精确机制仍然未知尚未完全理解。一些观察结果再次激发了人们对β细胞本身作为靶标的兴趣在这种情况下，最近发现 RNA 甲基化是一种可能引发疾病过程的组织。潜在的调节机制有助于细胞适应快速变化的能力环境提供了一种激发性的方法来研究β细胞在我们试图探究动态甲基化的变化。 RNA，特别是 β 细胞中的 N6-腺苷甲基化 (m6A)，以确定可能提供的特征导致 β 细胞死亡的过程的重要线索，我们将： 1)。从 1 型糖尿病模型中获得的胰岛细胞中的动态 RNA 甲基化变化 2) 确定人类胰岛和 β 细胞中 N6-甲基腺苷 (m6A) 变化的功能相关性；3) 探索 T1D 小鼠模型的胰岛细胞中 RNA 中额外甲基标记的变化将 T1D 模型中胰岛中观察到的 RNA 甲基化变化与蛋白质组学和基因进行对比从 T1D 患者获得的胰岛中的表达特征。