Calcium and the physiology of diabetes

钙与糖尿病的生理学

基本信息

批准号：
9923637
负责人：
ANDREW Robert MARKS
金额：
$ 40.5万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9923637
关键词：
Address Beta Cell Biochemical Biophysics Calcium Catecholaminergic Polymorphic Ventricular Tachycardia Cell membrane Clinical Clinical Trials DNA Sequence Alteration Diabetes Mellitus Drug Targeting Endoplasmic Reticulum Exercise Exhibits Extravasation Family Functional disorder Genetic Glucose Glucose Intolerance Glucose tolerance test Goals Health Heart failure Human ITPR1 gene Image Impaired cognition Impairment In Vitro Inherited Inositol Insulin Ion Channel Islets of Langerhans Knock-in Mouse Laboratories Lead Life Link Mediating Mediator of activation protein Metabolic Mitochondria Modeling Molecular Muscle Contraction Muscular Dystrophies Mutation Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Oral Organ Oxides Pathologic Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacological Treatment Pharmacology Phosphorylation Physiology Play Post-Translational Protein Processing Prevalence Production Regulation Research Resolution Role RyR1 RyR2 Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Serum Signal Transduction Stress Structure Structure of beta Cell of islet Sudden Death Tacrolimus Binding Protein 1A Testing Therapeutic Time United States base blood glucose regulation cell type dalton design endoplasmic reticulum stress glucose metabolism healthy volunteer human model impaired glucose tolerance improved in vivo insulin secretion member mitochondrial dysfunction molecular mass mouse model mutant new therapeutic target novel oxidation pancreas development prevent rare genetic disorder receptor response side effect skeletal muscle weakness small molecule sudden cardiac death translational impact virtual voltage

项目摘要

Type 2 diabetes mellitus (T2DM) is a major health concern worldwide, and the prevalence is increasing. Current therapeutics have potentially life-threatening side-effects. A better understanding of the molecular mechanisms underlying T2DM could lead to improved therapy. Calcium (Ca2+) plays a key role in the insulin secretion from pancreatic β cells in the islets of Langerhans. This project focuses on elucidating novel mechanisms underlying altered Ca2+ regulation that contribute to impaired insulin secretion. We show that in a rare genetic disorder intracellular Ca2+ leak via mutant type two ryanodine receptor/calcium release channels (RyR2) in pancreatic β cells is associated with glucose intolerance and decreased insulin secretion. The goal of this project is to use several murine models of T2DM to determine whether the observation that impaired insulin secretion is linked to RyR2-mediated intracellular Ca2+ leak is a generalized phenomenon in diverse models of T2DM. The approach will focus on examining the function of RyR2, a Ca2+ release channel located on the endoplasmic reticulum (ER) of many cell types including pancreatic β cells, in insulin release using biochemical, biophysical and metabolic tests. RyR2 can become leaky either due to genetic mutations or post-translational modifications (chiefly oxidation, nitrosylation and phosphorylation) all of which can impair stable closing of the channel resulting in pathological intracellular Ca2+ leak. The goal is to test the hypothesis that ER Ca2+ “leak” via RyR2 contributes to impaired insulin secretion in T2DM. The rationale is based on our recent finding that patients with leaky mutant RyR2 channels and an inherited form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia, CPVT) have abnormal glucose tolerance tests (GTT) and reduced insulin levels. Knock-in mice developed in the applicant’s laboratory harboring these CPVT RyR2 mutations have ER Ca2+ leak, abnormal GTT and reduced insulin levels, just like CPVT patients. The aims are: 1 Determine how leaky RyR2 channels cause mitochondrial dysfunction, and reduced insulin release.; 2) Does RyR2 channel dysfunction contribute to impaired insulin secretion in murine models of T2DM? Furthermore we will assess whether pharmacologic treatment with a new class of rycal drugs that fix leaky RyR2 channels, or genetic treatment that fixes leaky RyR2 channels, improves Ca2+ signaling, and insulin secretion in diverse models of T2DM? The goal of the project will be to provide mechanistic links between ER Ca2+ leak, ER stress, mitochondrial dysfunction, reduced insulin secretion and glucose intolerance, and has significant translational implications as leaky RyR2 may represent a novel therapeutic target for the treatment of T2DM.

2 型糖尿病 (T2DM) 是世界范围内的一个主要健康问题，并且患病率正在增加。目前的治疗方法具有潜在的危及生命的副作用，更好地了解分子机制。 T2DM 的潜在机制可能会改善治疗，钙 (Ca2+) 在治疗中发挥着关键作用。朗格汉斯胰岛中胰腺 β 细胞的胰岛素分泌作用该项目的重点是阐明。我们展示了导致胰岛素分泌受损的 Ca2+ 调节改变的新机制。在一种罕见的遗传性疾病中，细胞内 Ca2+ 通过突变型 2 型兰尼碱受体/钙泄漏胰腺 β 细胞中的释放通道 (RyR2) 与葡萄糖耐受不良和胰岛素减少有关该项目的目标是使用几种 T2DM 小鼠模型来确定是否存在分泌。胰岛素分泌受损与 RyR2 介导的细胞内 Ca2+ 渗漏有关的观察结果是该方法将重点检查 T2DM 不同模型中的普遍现象。 RyR2，一种 Ca2+ 释放通道，位于许多细胞类型的内质网 (ER) 上，包括胰岛β细胞，在胰岛素释放中可以通过生化、生物物理和代谢测试变成RyR2。由于基因突变或翻译后修饰（主要是氧化、亚硝基化和磷酸化）所有这些都会损害通道的稳定关闭，导致病理性细胞内 Ca2+ 泄漏的目的是检验 ER Ca2+ 通过 RyR2“泄漏”导致胰岛素受损的假设。其原理基于我们最近的发现，即携带 RyR2 渗漏突变的患者。通道和运动引起的猝死的遗传形式（儿茶酚胺能多态性室性心动过速 (CPVT) 具有异常的葡萄糖耐量试验 (GTT) 和胰岛素水平降低。申请人实验室开发的携带这些 CPVT RyR2 突变的敲入小鼠具有 ER Ca2+ 渗漏、GTT 异常和胰岛素水平降低，就像 CPVT 患者一样。目标是： 1 确定。 RyR2 通道渗漏如何导致线粒体功能障碍并减少胰岛素释放？ 2) RyR2 通道功能障碍会导致 T2DM 小鼠模型胰岛素分泌受损？此外，我们将评估是否可以使用一类新的 rycal 药物来修复渗漏 RyR2 通道，或修复 RyR2 通道渗漏的基因治疗，可改善 Ca2+ 信号传导和胰岛素该项目的目标是提供不同 T2DM 模型之间的机制联系。内质网 Ca2+ 渗漏、内质网应激、线粒体功能障碍、胰岛素分泌减少和葡萄糖耐受不良，以及具有重要的转化意义，因为渗漏的 RyR2 可能代表该疾病的新治疗靶点 T2DM 的治疗。