Mechanisms controlling Ca2+ dyshomeostasis in MH susceptible mice

MH 易感小鼠 Ca2 稳态失衡的控制机制

基本信息

  • 批准号:
    9480595
  • 负责人:
  • 金额:
    $ 23.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-11-01 至 2021-08-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The long-term goal of this research is to define the mechanisms responsible for the malignant hyperthermia syndrome. We have previously shown that a universal feature of RyR1 MH mutations is an increased resting myoplasmic free Ca2+ concentration ([Ca2+]i) and more recently that they are associated with an increased resting Na+ concentration ([Na+]i). We have also shown that sarcoplasmic reticulum (SR) leak is a factor in controlling myoplasmic Ca2+ concentration at rest working in concert with sarcolemmal channels, pumps and exchangers. Furthermore, because the amount of Ca2+ in internal stores is limited compared to the extracellular pool, after MH is triggered these same sarcolemmal channels, pumps and exchangers and perhaps others must be involved in the maintenance of the MH syndrome. Because of the observed increase in [Na+]i in MH muscles, TRPCs are the most likely candidates. Our immediate objectives are to use two mouse models that we have created, RyR1-R163C a mouse model of human MH, and CSQ1 null mice, which have an MH like phenotype, to study how mutations that alter intracellular Ca2+ homeostasis cause a fulminant MH response when exposed to volatile anesthetics. These models will allow us to test a unified general hypothesis applicable to any and all MH mutations regardless of the location of the mutation: MH is caused by conformational changes in RyR1 as a result of a mutation, or by conformational changes in RyR1 induced indirectly by a mutation in CaV1.1 or another protein closely associated with RyR1 (as demonstrated by an MH like phenotype in Casq1 null mice). A transformative concept to be investigated here is that a defect in signaling among Ca2+ release unit proteins leading to increased RyR1 leak is a common convergent pathway leading to all MH susceptibility. Hypothesis 1: MH susceptibility is the result of a conformational change in RyR1 caused either by a RyR1 mutation, or induced indirectly by mutations in other proteins closely associated with RyR1 which results in increased RyR1 SR Ca2+ leak and sarcolemmal Na+ and Ca2+ entry. Specific Aim 1. To determine the filling state of the SR and rate of SR Ca2+ leak in MH muscle fibers. Specific Aim 2. To determine the role of TRPCs in causing abnormalities in sarcolemmal Na+ and Ca2+ entry RyR1-R163C and CSQ1 null muscles and then to determine if skeletal muscle specific over-expression of a dominant negative non-conducting TRPC6 channel can modify RyR1-R163C's MH phenotype. Hypothesis 2: In addition to blocking RyR1 SR Ca2+ release, dantrolene abrogates the MH phenotype by modulating RyR1 SR Ca2+ leak and sarcolemmal Na+ and Ca2+ entry. Specific Aim 3. To determine the mechanisms by which dantrolene diminishes aberrant Ca2+ signaling. Successful completion of these specific Aims will provide a more comprehensive understanding of MH.


项目成果

期刊论文数量(0)
专著数量(0)
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Paul D Allen其他文献

Adenoidectomy may decrease the need for a third set of tympanostomy tubes in children.
腺样体切除术可能会减少儿童对第三组鼓室造口管的需求。
Polysomnogram outcomes in patients with laryngomalacia and obstructive sleep apnoea treated surgically versus non-surgically
手术治疗与非手术治疗的喉软化症和阻塞性睡眠呼吸暂停患者的多导睡眠图结果
  • DOI:
    10.1017/s0022215123000932
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Nicolas J. Casellas;Shalini Shah;S. Ravikumar;N. Vandjelovic;J. Faria;Paul D Allen;Margo McKenna Benoit
  • 通讯作者:
    Margo McKenna Benoit
Drug-induced sleep endoscopy findings in surgically-naïve obese vs non-obese children.
药物诱导的睡眠内窥镜检查在未接受过手术的肥胖儿童与非肥胖儿童中的发现。

Paul D Allen的其他文献

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{{ truncateString('Paul D Allen', 18)}}的其他基金

Mechanisms controlling Ca2+ dyshomeostasis in MH susceptible mice
MH 易感小鼠 Ca2 稳态失衡的控制机制
  • 批准号:
    10016079
  • 财政年份:
    2016
  • 资助金额:
    $ 23.76万
  • 项目类别:
Muscle: Excitation/Contraction Coupling Gordon Research Conference
肌肉:兴奋/收缩耦合戈登研究会议
  • 批准号:
    8254759
  • 财政年份:
    2011
  • 资助金额:
    $ 23.76万
  • 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
  • 批准号:
    7313034
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Administrative Core (Core A)
行政核心(核心A)
  • 批准号:
    7489219
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
  • 批准号:
    7493750
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Core B
核心B
  • 批准号:
    7436120
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Integral membrane protein overexpression using organ bioreactors
使用器官生物反应器过度表达整合膜蛋白
  • 批准号:
    7658832
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Heterozygous MH knock-in mice model Human MH susceptibility
杂合 MH 敲入小鼠模型 人类 MH 易感性
  • 批准号:
    7436116
  • 财政年份:
    2007
  • 资助金额:
    $ 23.76万
  • 项目类别:
Core B
核心B
  • 批准号:
    7075000
  • 财政年份:
    2006
  • 资助金额:
    $ 23.76万
  • 项目类别:
Uncovering the Molecular Basis of Malignant Hyperthermia
揭示恶性高热的分子基础
  • 批准号:
    7223472
  • 财政年份:
    2006
  • 资助金额:
    $ 23.76万
  • 项目类别:

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