Calcium and the physiology of diabetes

钙与糖尿病的生理学

基本信息

批准号：
10357858
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357858
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）在全球范围内是一个主要的健康问题，而且患病率正在增加。当前的治疗可能会威胁生命的副作用。更好地理解分子 T2DM的机制可能会改善治疗。钙（Ca2+）在 Langerhans胰岛中胰腺β细胞的胰岛素分泌。该项目着重于阐明基于的新机制改变了CA2+调节，导致胰岛素分泌受损。我们显示在罕见的遗传疾病中，细胞内Ca2+通过突变体两型ryanodine接收器/钙胰腺β细胞中的释放通道（RYR2）与葡萄糖耐药性和改善的胰岛素有关分泌。该项目的目的是使用几种T2DM的鼠模型来确定是否是否观察到受损的胰岛素分泌与RYR2介导的细胞内Ca2+泄漏有关 T2DM潜水模型中的广义现象。该方法将着重于检查 RYR2，一个Ca2+释放通道，位于许多细胞类型的内质网（ER）上胰腺β细胞，在使用生化，生物物理和代谢检测的胰岛素释放中。 RYR2可以成为由于基因突变或翻译后修饰而泄漏（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，从而导致病理内细胞内 CA2+泄漏。目的是检验以下假设：ER Ca2+通过RYR2泄漏有助于胰岛素受损 T2DM的分泌。理由是基于我们最近的发现，即渗漏突变体RYR2患者通道和一种遗传性运动引起的猝死形式（儿茶酚胺能多态性心室心动过速，CPVT）具有异常的葡萄糖耐受性测试（GTT）和胰岛素水平降低。携带这些CPVT RYR2突变的申请人实验室中开发的敲门小鼠具有ER CA2+泄漏，GTT异常和胰岛素水平降低，就像CPVT患者一样。目的是：1确定 RYR2通道漏水如何引起线粒体功能障碍和减少胰岛素释放。 2）做 RYR2通道功能障碍有助于T2DM的鼠模型中的胰岛素分泌受损？此外，我们将评估使用新的Rycal药物来解决漏水的药物治疗 RYR2通道或固定RYR2通道的遗传处理可改善CA2+信号传导和胰岛素 T2DM的潜水员模型中的分泌？该项目的目的是提供机械联系 ER CA2+泄漏，ER应力，线粒体功能障碍，胰岛素分泌减少和葡萄糖耐含量以及具有显着的翻译含义，因为泄漏的RYR2可能代表 T2DM的处理。