The role of retromer in Parkinson's Disease

逆转录酶在帕金森病中的作用

• 批准号: 8441732
• 负责人: RICHARD FINE
• 金额: --
• 依托单位: EDITH NOURSE ROGERS MEMORIAL VETERANS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441732
• 关键词: Advisory Committees; Affect; Age; Back; Biochemical; Biochemical Pathway; Biochemical Process; Biological Models; CMV promoter; Carrier Proteins; Cell Line; Cell physiology; Cells; Cloning; Complementary DNA; DNA; Data; Development; Diagnostic; Disease; Disease Progression; Disease model; Elderly; Endosomes; Experimental Models; Family member; Free Radicals; Future; Gene Expression; Gene Expression Profile; Genes; Goals; Grant; Homeostasis; Individual; Investigation; LRRK2 gene; Letters; Mediating; Methods; Mission; Mitochondria; Modeling; Molecular; Mutagenesis; Mutate; Mutation; N-terminal; Nerve Degeneration; Neurons; Onset of illness; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patient Care; Pattern; Phenotype; Plasmids; Play; Population; Process; Production; Protein Secretion; Proteins; Research; Risk; Role; Series; Signal Transduction; Small Interfering RNA; Testing; Vertebral column; Veterans; Work; age related; alpha synuclein; expression vector; health administration; in vitro Model; knock-down; mutant; novel; novel therapeutics; parkin gene/protein; peroxisome; public health relevance; receptor recycling; research study; therapeutic development; trans-Golgi Network; vector

DESCRIPTION (provided by applicant): This pilot proposal will expand on the recent finding that a dominant mutation in the retromer protein VPS35 causes Parkinson's disease (PD). Retromer proteins are involved in transport of proteins from the endosomes back to the trans-Golgi network. We propose to develop an in vitro model and to perform a series of analyses in order to identify the molecular mechanism(s) by which the mutant form of VPS35 causes PD. To create the model the PD mutant VPS35 protein will be expressed in a cell lines. Analysis will be performed on several levels. We will examine retromer function by analyzing receptor recycling in the cells expressing the PD mutant VPS35. Cells expressing the PD mutant VPS35 will be analyzed for biochemical changes such as changes in mitochondrial activity and protein secretion. Gene array analysis will be performed to identify potential changes in gene expression. The development of a novel in vitro model of PD will provide an opportunity to identify new molecular pathways and new avenues for therapeutic development.

描述（由申请人提供）： 这项试点提案将扩展最近的发现，即逆转录蛋白VPS35中的显性突变导致帕金森病（PD）。逆转录蛋白质参与蛋白质从内体回到高尔基体网络的转运。我们建议开发一种体外模型，并进行一系列分析，以确定VPS35突变形式导致PD的分子机制。为了创建模型，PD突变VPS35蛋白将在细胞系中表达。将在多个层面上进行分析。我们将通过分析表达PD突变VPS35的细胞中的受体再循环来检查逆转录功能。将分析表达PD突变VPS35的细胞的生化变化，例如线粒体活性和蛋白质分泌的变化。将进行基因阵列分析，以确定基因表达的潜在变化。新型PD体外模型的开发将为识别新的分子途径和治疗开发的新途径提供机会。