SIMPLE-regulated trafficking and peripheral neuropathy

 描述(由申请人提供)：囊泡运输对细胞功能和生存至关重要，解除对囊泡运输的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囊泡运输在正常生理中是如何控制的，以及这个过程在疾病状态下是如何变得失调的。Charcot-Marie-Tooth病(CMT)是最常见的遗传性周围神经病，已有125多年的历史，但其发病机制尚不清楚，目前尚无有效的治疗方法。人类遗传学研究表明，SIMPLE是一种功能未知的普遍表达的蛋白质，其错义突变会导致一种常染色体显性遗传的外周神经病，称为CMT 1C型。SIMPLE与CMT的联系强调了了解这种未被研究的蛋白质功能的重要性，并为研究引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是一种早期的内体膜蛋白，参与调节内小体到溶酶体的运输，并建立了第一个表达与疾病相关的人类SIMPLE突变蛋白的CMT1C小鼠模型。在这个项目中，申请人的团队将在他们最新研究的基础上，结合生物化学、分子生物学、细胞生物学、蛋白质组学和小鼠遗传学方法来确定调控囊泡运输的简单作用机制，并阐明简单突变导致周围神经病的致病途径。这一项目的成功完成将增进我们对微泡运输的基本机制的了解，并为开发有效的治疗周围神经病和其他人类疾病所需的有用信息。

 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.