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:
- 金额:$ 40.5万
- 依托单位:
- 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:
- 关键词:AddressBeta CellBiochemicalBiophysicsCalciumCatecholaminergic Polymorphic Ventricular TachycardiaCell membraneClinicalClinical TrialsDNA Sequence AlterationDiabetes MellitusDrug TargetingEndoplasmic ReticulumExerciseExhibitsExtravasationFamilyFunctional disorderGeneticGlucoseGlucose IntoleranceGlucose tolerance testGoalsHealthHeart failureHumanITPR1 geneImageImpaired cognitionImpairmentIn VitroInheritedInositolInsulinIon ChannelIslets of LangerhansKnock-in MouseLaboratoriesLeadLifeLinkMediatingMediator of activation proteinMetabolicMitochondriaModelingMolecularMuscle ContractionMuscular DystrophiesMutationNerve DegenerationNon-Insulin-Dependent Diabetes MellitusOralOrganOxidesPathologicPatientsPeptide HydrolasesPharmaceutical PreparationsPharmacological TreatmentPharmacologyPhosphorylationPhysiologyPlayPost-Translational Protein ProcessingPrevalenceProductionRegulationResearchResolutionRoleRyR1RyR2Ryanodine Receptor Calcium Release ChannelRyanodine ReceptorsSerumSignal TransductionStressStructureStructure of beta Cell of isletSudden DeathTacrolimus Binding Protein 1ATestingTherapeuticTimeUnited Statesbaseblood glucose regulationcell typedaltondesignendoplasmic reticulum stressglucose metabolismhealthy volunteerhuman modelimpaired glucose toleranceimprovedin vivoinsulin secretionmembermitochondrial dysfunctionmolecular massmouse modelmutantnew therapeutic targetnoveloxidationpancreas developmentpreventrare genetic disorderreceptorresponseside effectskeletal muscle weaknesssmall moleculesudden cardiac deathtranslational impactvirtualvoltage
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
T2DM 的潜在机制可能会导致治疗的改善。钙(Ca2+)在
朗格汉斯岛的胰腺 β 细胞分泌胰岛素。该项目的重点是阐明
Ca2+ 调节改变导致胰岛素分泌受损的新机制。我们展示
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
分泌。该项目的目标是使用几种 T2DM 小鼠模型来确定是否
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
T2DM 不同模型中的普遍现象。该方法将侧重于检查
RyR2,一种 Ca2+ 释放通道,位于许多细胞类型的内质网 (ER) 上,包括
使用生化、生物物理和代谢测试,检测胰腺 β 细胞在胰岛素释放中的作用。 RyR2可以变成
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。目标是检验 ER Ca2+ 通过 RyR2“泄漏”导致胰岛素受损的假设
T2DM 中的分泌。其基本原理是基于我们最近的发现,携带漏突变 RyR2 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) 是否
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,或修复泄漏的 RyR2 通道的基因治疗,改善 Ca2+ 信号传导和胰岛素
多种 T2DM 模型中的分泌?该项目的目标是在
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 可能代表了一种新的治疗靶点
T2DM 的治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANDREW Robert MARKS其他文献
ANDREW Robert MARKS的其他文献
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{{ truncateString('ANDREW Robert MARKS', 18)}}的其他基金
Ryanodine receptor structure and function in heart failure
Ryanodine 受体结构和心力衰竭中的功能
- 批准号:
10628917 - 财政年份:2023
- 资助金额:
$ 40.5万 - 项目类别:
Summer Program for Under Represented Students (SPURS)
弱势学生暑期项目 (SPURS)
- 批准号:
10583050 - 财政年份:2022
- 资助金额:
$ 40.5万 - 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
- 批准号:
10669557 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
- 批准号:
10115469 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
Training in Cardiovascular Sciences for Under Represented Students
为代表性不足的学生提供心血管科学培训
- 批准号:
10397516 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
Calcium and the Pathophysiology of Neurodegenerative Disorders
钙与神经退行性疾病的病理生理学
- 批准号:
10052965 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
Structure-function analysis for elucidating pathogenicity of cardiac ryanodine receptor genetic variants
结构功能分析阐明心脏兰尼碱受体遗传变异的致病性
- 批准号:
10407960 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Ryanodine Receptor Defects in Cardiomyopathy Caused by Lamin A/C Gene Mutations
Lamin A/C 基因突变引起的心肌病中的 Ryanodine 受体缺陷
- 批准号:
9904328 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
Ryanodine Receptor Defects in Cardiomyopathy Caused by Lamin A/C Gene Mutations
Lamin A/C 基因突变引起的心肌病中的 Ryanodine 受体缺陷
- 批准号:
10376824 - 财政年份:2019
- 资助金额:
$ 40.5万 - 项目类别:
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