THE ROLE OF GAP JUNCTIONS IN OXIDATIVE NEURODEGENERATION IN CEREBELLUM

间隙连接在小脑氧化性神经变性中的作用

• 批准号: 7720200
• 负责人: DINGBO D LIN
• 金额: $ 3.22万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720200
• 关键词: Accounting; Age of Onset; Animals; Apoptosis; Apoptotic; Binding; Cell Death; Cells; Cerebellum; Computer Retrieval of Information on Scientific Projects Database; Connexins; Defect; Docking; Drug Design; Failure; Funding; Gap Junctions; Grant; Human; Hyperbaric Oxygen; Institution; Knock-out; Knockout Mice; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; Peptides; Play; Process; Proteins; Purkinje Cells; Research; Research Personnel; Resources; Role; Signal Transduction; Source; Spinocerebellar Ataxias; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; mouse model; prevent; protein kinase C gamma; relating to nervous system; response; restoration

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. The passage of apoptotic signals through gap junctions has been implicated in oxidative cell death and neurodegenerative disorders. Gap junction proteins play important roles in cerebellum. Protein kinase C gamma (PKCgamma) is a neuronal specific PKC. Activated PKCgamma phosphorylates and inhibits gap junctions, a process which is controlled by a cell oxidative state. C1B1 peptides activate PKCgamma by competitively binding to its docking protein 14-3-3. Mutations in PKCgamma cause spinocerebellar ataxia type 14 (SCA-14), an autosomal, dominant neurodegenerative disorder in humans with onset ages of three to thirty years. Thus, mutations of PKCgamma would cause a failure of the cell or animal to respond to oxidative stress by inhibition of gap junctions, which subsequently results in oxidative cell death. In this proposal we will determine how gap junctions are controlled by PKCgamma activation and what the effect of inhibition of gap junctions on neural apoptosis. We will also characterize the defects in cerebellar response to oxidative stress in the PKCgamma H101Y SCA14 transgenic mouse models. We have demonstrated that exposure of PKCgamma knockout mice to hyperbaric oxygen results in severe loss of Purkinje cells, an effect not observed in control mice. Overexpression of the PKCgamma H101Y SCA14 mutation leads to significant loss of Purkinje cells in transgenic mice. The improper control of gap junctions in PKCgamma knockout and/or transgenic mice may account for Purkinje neuron degeneration. This information will provide direction for the design of drugs to delay or prevent oxidative neurodegeneration by restoration of control of gap junctions.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞凋亡信号通过缝隙连接的传递与细胞氧化死亡和神经退行性疾病有关。缝隙连接蛋白在小脑中发挥着重要作用。蛋白激酶C-γ(PKC-Gamma)是一种神经元特异性的PKC。激活的PKCGamma磷酸化并抑制缝隙连接，这是一个由细胞氧化状态控制的过程。C1B1多肽通过竞争性地与其停靠蛋白14-3-3结合来激活PKCGamma。PKCGamma基因突变导致脊髓小脑性共济失调14型(SCA-14)，这是一种常染色体显性神经退行性疾病，发病年龄在3到30岁之间。因此，PKCGamma的突变会导致细胞或动物无法通过抑制缝隙连接来应对氧化应激，从而导致细胞氧化死亡。在这项提案中，我们将确定缝隙连接是如何被PKCGamma激活控制的，以及抑制缝隙连接对神经细胞凋亡的影响。我们还将在PKCGamma H101Y SCA14转基因小鼠模型中表征小脑对氧化应激反应的缺陷。我们已经证明，PKCGamma基因敲除小鼠暴露在高压氧中会导致浦肯野细胞的严重损失，这一影响在对照组小鼠中没有观察到。在转基因小鼠中过表达PKCGamma H101Y SCA14突变会导致浦肯野细胞的显著丧失。在PKCGamma基因敲除和/或转基因小鼠中，缝隙连接控制不当可能是浦肯野神经元变性的原因。这些信息将为通过恢复对缝隙连接的控制来延缓或防止氧化性神经变性的药物设计提供方向。