Cellular and Biophysical Mechanisms of CMTX

描述（由申请人提供）：连接蛋白32（Cx 32 Y）是一种间隙连接蛋白，存在于髓鞘形成的许旺细胞的结旁环和施密特-兰特曼切口中。编码这种间隙连接蛋白的基因突变导致CMTX，一种X连锁形式的Charcot-MarieTooth（CXMT）疾病，一组遗传性周围神经病。这项工作的假设是，在CMTX患者中发现的Cx 32突变改变了Cx 32的功能特性，因此它不再提供重要的许旺细胞通讯途径。基于最近的观察，至少一种突变可以赋予通道特性，其可能对表达突变蛋白的细胞有毒。本提案中概述的实验将检查含有CMTX突变的Cx 32通道的功能表达和生物物理特性的改变。还将检查CMTX突变对间隙连接蛋白运输的影响。研究结果将与文献中的临床数据和治疗CXMT患者的神经科医生提供的数据相关联。更好地了解与CMTX相关的Cx 32的特定功能改变，才能设计出合理的治疗方法。此外，更完整地了解在这种疾病中改变的Cx 32依赖过程可能为Cx 32在正常雪旺细胞中的特定作用提供线索。我的担保人M.V.L.博士班尼特和共同申办者T. A.博士Bargiello先生，继续为我在申请中概述的工作和我的职业发展提供强有力的支持。我的K 08补助金将持续两年，这将使我能够继续向完全独立过渡，并在大约12-18个月内提交我最强烈的R 01补助金申请。

DESCRIPTION (provided by applicant): Connexin 32 (Cx32Y) is a gap junction protein found in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells. Mutations in the gene encoding this gap junction protein lead to CMTX, an X linked form of Charcot-MarieTooth (CXMT) disease, a group of inherited peripheral neuropathies. The hypothesis underlying this work is that mutations in Cx32 found in patients with CMTX alter the functional properties of Cx32 so it can no longer provide a vital Schwann cell communication pathway. Based on recent observations at least one mutation may confer channel properties that could be toxic to cells in which the mutant protein is expressed. The experiments outlined in this proposal will examine alterations in functional expression and biophysical properties of Cx32 channels containing CMTX mutations. The effects of CMTX mutations on trafficking of gap junction proteins will also be examined. Findings will be correlated with both clinical data from the literature and with data provided by neurologists who care for patients with CXMT. A better understanding of the specific functional alterations in Cx32 associated with CMTX is needed before rational therapies for this disorder can be devised. In addition, a more complete understanding of the Cx32 dependent processes that are altered in this disease may provide clues to the specific roles of Cx32 in the normal Schwann cell. My sponsor, Dr. M.V.L. Bennett and co-sponsor, Dr. T.A. Bargiello, continue to provide strong support for the work outlined in this application and for my career development in general. The additional support that will be provided by a two-years continuation of my K08 grant will allow me to continue my transition to full independence and to submit my strongest application for an R01 grant within approximately 12-18 months.