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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）是世界范围内的主要健康问题，患病率正在上升。