SIMPLE-regulated trafficking and peripheral neuropathy

SIMPLE调节的运输和周围神经病变

基本信息

批准号：
9029639
负责人：
LIAN LI
金额：
$ 33.27万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9029639
关键词：
Affect Animal Model Antibodies Autophagocytosis Biochemical Biogenesis Biological Biological Process Cell Membrane Proteins Cell Survival Cell membrane Cell model Cell physiology Cells Charcot-Marie-Tooth Disease Complex Data Defect Development Disease Endosomes Extracellular Space Functional disorder Gene Duplication Genetic study Goals Health Human Human Genetics Induced Mutation Inherited Knowledge Link Lysosomes Mediating Mediator of activation protein Membrane Membrane Proteins Missense Mutation Modeling Molecular Multivesicular Body Mus Mutation Myelin Names Neurodegenerative Disorders Neurons Neuropathy Nuclear Pathogenesis Pathway interactions Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Phenotype Physiology Process Proteins Proteomics Regulation Research Role Schwann Cells Signal Transduction Sorting - Cell Movement Testing effective therapy follow-up genetic approach human disease insight mouse model mutant nanosized novel novel therapeutics overexpression phosphatidylinositol 3-phosphate public health relevance research study trafficking vesicular release

项目摘要

DESCRIPTION (provided by applicant): Vesicular trafficking is crucial to cell function and survival, and deregulation of vesicular trafficking is associated with many human diseases, including neurodegenerative disease and peripheral neuropathy. The long-term goal of this research is to understand, at the molecular level, how vesicular trafficking is controlled in norma physiology and how this process becomes dysregulated in disease states. Charcot- Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy that has been known for more than 125 years, yet the pathogenic mechanisms underlying this disease remain unclear and there are currently no effective treatment for peripheral neuropathy. Human genetic studies reveal that missense mutations in SIMPLE, a ubiquitously expressed protein of unknown function, cause an autosomal dominant form of peripheral neuropathy known as CMT type 1C. The connection of SIMPLE to CMT underscores the importance of understanding the function of this understudied protein and opens up new avenues for investigating the molecular mechanisms that trigger peripheral neuropathy. Recently, the applicant's team found that SIMPLE is an early endosomal membrane protein involved in regulation of endosome-to- lysosome trafficking and generated the first CMT1C mouse model expressing a disease-linked human SIMPLE mutant protein. In this project, the applicant's team will build on their recent studies and use a combination of biochemical, molecular biological, cell biological, proteomic, and mouse genetic approaches to define the mechanisms of SIMPLE action in regulating vesicular trafficking and elucidate the pathogenic pathways by which SIMPLE mutations cause peripheral neuropathy. Successful completion of this project will advance our knowledge of the fundamental mechanisms governing vesicular trafficking and provide useful information needed for development of effective therapies to treat peripheral neuropathy and other human diseases with disturbed vesicular trafficking.

描述（由适用提供）：囊泡运输对细胞功能和存活至关重要，囊泡运输的放松管制与许多人类疾病有关，包括神经退行性疾病和周围神经病。这项研究的长期目标是在分子水平上了解如何在Norma生理学中控制囊泡贩运以及在疾病状态下该过程如何失调。 Charcot- Marie-Tooth病（CMT）是最常见的遗传性周围神经病，已有125年以上的历史，但是这种疾病的致病机制尚不清楚，目前尚无对周围神经病的有效治疗方法。人类遗传研究表明，简单的，普遍表达的功能的蛋白质中的错义突变导致外周神经病的常染色体显性形式，称为CMT 1C型CMT。简单到CMT的联系了解理解这种理解蛋白质功能的重要性，并为研究触发周围神经病的分子机制开辟了新的途径。最近，申请人的团队发现，简单是一种早期的内体膜蛋白，涉及内体 - 溶液体运输的调节，并生成了表达疾病连接的人类简单突变蛋白的第一个CMT1C小鼠模型。在该项目中，申请人的团队将基于他们最近的研究，并结合生化，分子生物学，细胞生物学，蛋白质组学和小鼠遗传学方法来定义调节囊泡贩运和阐明简单突变导致外周神经疗法的致病途径的简单作用机制。该项目的成功完成将提高我们对囊泡贩运的基本机制的了解，并提供有效疗法的有用信息，以治疗外周神经病和其他人类疾病，并具有干扰的囊泡贩运。