Calcium and the physiology of diabetes

钙与糖尿病的生理学

基本信息

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。

项目成果

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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:
Calcium and the physiology of diabetes
钙与糖尿病的生理学
  • 批准号:
    10357858
  • 财政年份:
    2019
  • 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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β细胞破坏的生化机制
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通过溴结构域抑制保护 β 细胞的生化机制
  • 批准号:
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  • 财政年份:
    2018
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Biochemical mechanisms of beta cell protection through bromodomain inhibition
通过溴结构域抑制保护 β 细胞的生化机制
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  • 财政年份:
    2018
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β细胞破坏的生化机制
  • 批准号:
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Biochemical basis of islet beta-cell compensation and failure in normal pregnancy and gestational diabetes mellitus
正常妊娠和妊娠糖尿病中胰岛β细胞代偿和失败的生化基础
  • 批准号:
    nhmrc : 418077
  • 财政年份:
    2007
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    $ 40.5万
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    NHMRC Project Grants
BIOCHEMICAL MECHANISM OF BETA-CELL DESTRUCTION
β 细胞破坏的生化机制
  • 批准号:
    6489690
  • 财政年份:
    1998
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Biochemical Mechanism of Beta-Cell Destruction
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    1998
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