TRPC1, CALCIUM AND PARKINSON'S DISEASE

TRPC1、钙和帕金森病

基本信息

  • 批准号:
    8360139
  • 负责人:
  • 金额:
    $ 24.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-06-01 至 2012-07-14
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra pars compacta. A number of pathogenic factors have been implicated in the degeneration of dopaminergic neurons in the substantia nigra including generation of free radicals, impairment of mitochondrial function, disturbances of calcium homeostasis, and apoptosis. It could be hypothesized that a common factor should be involved in the pathogenesis of PD. Calcium being a common factor in all the above processes raises the possibility that this could be the possible link. Also calcium homeostasis plays an important role in stimulating and inhibiting neuronal cell death, and calcium mediates apoptosis. Thus, depending on spatial and temporal factors, calcium channels may have a salutary effect on conditions such as PD in which apoptosis may be the ultimate mode of cell death. Calcium enters the cytoplasm from two sources; it is either released from the intracellular stores, or it enters through the plasma membrane. Depletion of the intracellular stores leads to the opening of plasma membrane calcium channels which are known as store-operated calcium entry (SOCE) channels. Recently, a mammalian homologue of the Drosophila trp gene, TRPC1, has been suggested as a SOCE channel. Moreover, our recent data indicate that TRPC1 protein levels and its plasma membrane localization is significantly decreased after treatment with drugs known to cause PD (MPP+ or salsolinol). Importantly, overexpression of TRPC1 protected SH-SY5Y neuronal cells against the cellular toxicity elicited by MPP+ and salsolinol. The protection exhibited by TRPC1 was dependent on its calcium influx properties and the translocation of pro-apoptotic proteins from the endoplasmic reticulum to mitochondria. These data demonstrate, for the first time, that TRPC1 has a role in protecting dopaminergic neurons. Nevertheless, the role of TRPC1 in vivo has yet to be elucidated and the mechanisms by which TRPC1 protects dopaminergic neurons are not known. Thus, we propose to extend our knowledge in animal models (TRPC1 knockout mice, and PD mouse models) and determine the role of TRPC1 in PD by identifying mechanism(s) by which TRPC1 protects dopaminergic neurons.
这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的, 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量, 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 帕金森病(PD)是一种进行性神经退行性疾病,与黑质致密部多巴胺能神经元的选择性丢失有关。许多致病因素参与了黑质多巴胺能神经元的变性,包括自由基的产生、线粒体功能的损害、钙稳态的紊乱和细胞凋亡。这可能是一个共同的因素参与了帕金森病的发病机制。钙是上述所有过程中的一个共同因素,这可能是可能的联系。此外,钙稳态在刺激和抑制神经细胞死亡方面起着重要作用,钙离子介导了细胞凋亡。因此,依赖于空间和时间因素,钙通道可能对帕金森病等条件有有益的影响,在这种情况下,细胞凋亡可能是细胞死亡的最终模式。钙从两个来源进入细胞质;它要么从细胞内储存物中释放出来,要么通过质膜进入。细胞内钙离子的耗尽导致质膜钙通道的开放,这就是所谓的钙离子通道(SOCE)。最近,果蝇Trp基因的哺乳动物同源基因TRPC1被认为是SOCE通道。此外,我们最近的数据表明,经已知的引起PD的药物(MPP+或沙龙醇)治疗后,TRPC1蛋白水平及其质膜定位显著降低。重要的是,TRPC1的过表达保护SH-SY5Y神经元细胞免受MPP+和丹参素的细胞毒性。TRPC1的保护作用依赖于它的钙内流特性和促凋亡蛋白从内质网到线粒体的移位。这些数据首次证明,TRPC1具有保护多巴胺能神经元的作用。然而,TRPC1在体内的作用尚未阐明,TRPC1保护多巴胺能神经元的机制尚不清楚。因此,我们建议在动物模型(TRPC1基因敲除小鼠和PD小鼠模型)中扩展我们的知识,并通过确定TRPC1保护多巴胺能神经元的机制(S)来确定TRPC1在帕金森病中的作用。

项目成果

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Brij B Singh其他文献

Evidence for the nitrate assimilation-dependent nitrite excretion in cyanobacterium Nostoc MAC
蓝藻发菜 MAC 中硝酸盐同化依赖性亚硝酸盐排泄的证据

Brij B Singh的其他文献

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{{ truncateString('Brij B Singh', 18)}}的其他基金

Glycolytic metabolites, Calcium entry and Sjogren’s syndrome
糖酵解代谢物、钙进入和干燥综合征
  • 批准号:
    10583678
  • 财政年份:
    2022
  • 资助金额:
    $ 24.87万
  • 项目类别:
Glycolytic metabolites, Calcium entry and Sjogren’s syndrome
糖酵解代谢物、钙进入和干燥综合征
  • 批准号:
    10706579
  • 财政年份:
    2022
  • 资助金额:
    $ 24.87万
  • 项目类别:
TRPC1, Calcium, and Saliva Secretion
TRPC1、钙和唾液分泌
  • 批准号:
    9900137
  • 财政年份:
    2019
  • 资助金额:
    $ 24.87万
  • 项目类别:
Epigenetic regulations in Sjogern's syndrome
干燥综合征的表观遗传调控
  • 批准号:
    9604635
  • 财政年份:
    2017
  • 资助金额:
    $ 24.87万
  • 项目类别:
Epigenetic regulations in Sjogern's syndrome
干燥综合征的表观遗传调控
  • 批准号:
    10205023
  • 财政年份:
    2017
  • 资助金额:
    $ 24.87万
  • 项目类别:
Ceramide membrane microdomains regulate cytokine secretion
神经酰胺膜微结构域调节细胞因子分泌
  • 批准号:
    8469388
  • 财政年份:
    2012
  • 资助金额:
    $ 24.87万
  • 项目类别:
Ceramide membrane microdomains regulate cytokine secretion
神经酰胺膜微结构域调节细胞因子分泌
  • 批准号:
    8374310
  • 财政年份:
    2012
  • 资助金额:
    $ 24.87万
  • 项目类别:
TRPC1, CALCIUM AND PARKINSON'S DISEASE
TRPC1、钙和帕金森病
  • 批准号:
    8168380
  • 财政年份:
    2010
  • 资助金额:
    $ 24.87万
  • 项目类别:
TRPC1, CALCIUM AND PARKINSON'S DISEASE
TRPC1、钙和帕金森病
  • 批准号:
    7959948
  • 财政年份:
    2009
  • 资助金额:
    $ 24.87万
  • 项目类别:
TRPC1, CALCIUM AND PARKINSON'S DISEASE
TRPC1、钙和帕金森病
  • 批准号:
    7720884
  • 财政年份:
    2008
  • 资助金额:
    $ 24.87万
  • 项目类别:

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