Cellular and Biophysical Mechanisms of CMTX

描述(申请人提供)：连接蛋白32(Cx32Y)是一种间隙连接蛋白，存在于髓鞘雪旺细胞的结旁环和Schmidt-Lantermann切牙中。这种缝隙连接蛋白编码基因的突变导致了CMTX，一种X连锁的Charcot-MarieTooth(CXMT)病，一组遗传性周围神经疾病。这项工作背后的假设是，在CMTX患者中发现的Cx32突变改变了Cx32的功能特性，因此它不再提供重要的雪旺细胞通讯途径。根据最近的观察，至少有一个突变可能赋予表达突变蛋白的细胞有毒的通道特性。该提案中概述的实验将检查包含CMTX突变的Cx32通道的功能表达和生物物理性质的变化。还将研究CMTX突变对缝隙连接蛋白运输的影响。这些发现将与文献中的临床数据和护理CXMT患者的神经科医生提供的数据相关联。在设计合理的治疗方法之前，需要更好地了解与CMTX相关的Cx32基因的特定功能变化。此外，更完整地了解Cx32在本病中的依赖过程可能为了解Cx32在正常雪旺细胞中的具体作用提供线索。我的赞助人M.V.L.Bennett博士和共同赞助人T.A.Bargiello博士继续为本申请表中概述的工作和我总体的职业发展提供强有力的支持。我的K08助学金延续两年将提供额外的支持，这将使我能够继续过渡到完全独立，并在大约12-18个月内提交我最强烈的R01助学金申请。

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.