SIMPLE-regulated trafficking and peripheral neuropathy

 描述（由申请人提供）：囊泡运输对细胞功能和存活至关重要，囊泡运输的失调与许多人类疾病相关，包括神经退行性疾病和周围神经病变。这项研究的长期目标是在分子水平上了解囊泡运输在正常生理学中是如何控制的，以及这个过程在疾病状态下是如何失调的。Charcot-Marie-Tooth病（CMT）是已知超过125年的最常见的遗传性周围神经病，然而，该疾病的致病机制仍然不清楚，并且目前没有有效的治疗周围神经病的方法。人类遗传学研究表明，错义突变的SIMPLE，一种普遍表达的蛋白质的未知功能，导致常染色体显性形式的周围神经病变称为CMT型1C。SIMPLE与CMT的联系强调了了解这种未充分研究的蛋白质功能的重要性，并为研究触发周围神经病变的分子机制开辟了新的途径。最近，申请人的团队发现SIMPLE是参与调节内体至溶酶体运输的早期内体膜蛋白，并产生了表达疾病相关的人SIMPLE突变蛋白的第一个CMT 1C小鼠模型。在该项目中，申请人的团队将建立在他们最近的研究基础上，并使用生物化学，分子生物学，细胞生物学，蛋白质组学和小鼠遗传学方法的组合来定义SIMPLE在调节囊泡运输中的作用机制，并阐明SIMPLE突变导致周围神经病变的致病途径。本项目的成功完成将促进我们对囊泡运输基本机制的了解，并为开发治疗周围神经病变和其他囊泡运输紊乱的人类疾病的有效疗法提供有用的信息。

 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.