TRPC1, CALCIUM AND PARKINSON'S DISEASE

TRPC1、钙和帕金森病

• 批准号: 8168380
• 负责人: Brij B Singh
• 金额: $ 22.29万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168380
• 关键词: 1-Methyl-4-phenylpyridinium; Aftercare; Animal Model; Apoptosis; Calcium; Calcium Channel; Cell Death; Cell membrane; Cells; Computer Retrieval of Information on Scientific Projects Database; Cytoplasm; Data; Drosophila genus; Endoplasmic Reticulum; Exhibits; Free Radicals; Funding; Generations; Genes; Grant; Homeostasis; Homologous Gene; Impairment; Institution; Knockout Mice; Knowledge; Link; Mediating; Mitochondria; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Play; Process; Property; Research; Research Personnel; Resources; Role; Source; Substantia nigra structure; TRPC1 protein; Time; Toxic effect; United States National Institutes of Health; dopaminergic neuron; in vivo; mouse model; neuron loss; overexpression; pars compacta; pro-apoptotic protein; salsolinol

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 帕金森氏病（PD）是一种进行性神经退行性疾病，与在底虫中选择性丧失多巴胺能神经元有关。 许多致病因素与黑质中多巴胺能神经元的变性有关，包括产生自由基的产生，线粒体功能损害，钙稳态的障碍和凋亡。 可以假设，PD的发病机理应涉及一个共同的因素。 在上述所有过程中，钙是一个共同的因素，这增加了这可能是可能的链接的可能性。 钙稳态也在刺激和抑制神经元细胞死亡中起重要作用，钙介导凋亡。 因此，根据空间和时间因素，钙通道可能对诸如PD诸如细胞凋亡可能是细胞死亡的最终模式之类的条件有巨大影响。 钙从两个来源进入细胞质。它要么从细胞内存储中释放，要么通过质膜进入。 细胞内存储的耗竭会导致质膜钙通道的开放，这些通道被称为储存的钙进入（SOCE）通道。 最近，已建议将果蝇TRP基因TRPC1的哺乳动物同源物作为SOCE通道。 此外，我们最近的数据表明，用已知引起PD的药物（MPP+或Salsolinol）处理后TRPC1蛋白水平及其质膜定位显着降低。 重要的是，TRPC1的过表达保护了SY5Y神经元细胞，以免受MPP+和Salsolinol引起的细胞毒性。 TRPC1所表现出的保护取决于其钙的涌入特性以及促凋亡蛋白从内质网向线粒体的易位。 这些数据首次证明TRPC1在保护多巴胺能神经元中起作用。 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，我们建议通过识别TRPC1保护多巴胺能神经元的机制来扩展动物模型（TRPC1敲除小鼠和PD小鼠模型）的知识，并确定TRPC1在PD中的作用。