Connexin 32 Mutations in X-Linked CMT

X连锁Charcot Marie-Tooth病(CMTX)是一种与突变相关的遗传性周围神经病变 缝隙连接蛋白连接蛋白32(Cx32)。这项提议的中心原则是 Cx32形成的离子通道的功能特性可以引起CMTX。此外，我们建议 要了解突变和疾病之间的联系，我们必须探索诱导的具体性质 在通道门控、渗透率和地层控制方面存在缺陷。尽管特定对象之间的关联 离子通道和神经肌肉疾病的突变通常是引人注目的，这是 缺陷可以通过临床测量、形态检查或流行病学来保持不被发现。这些研究 )是申请人先前探索这种联系的工作的直接和合乎逻辑的延续 )CMTX和控制缝隙连接蛋白的基因突变之间的关系；它们建立在之前的努力基础上 细胞和亚细胞水平的功能缺陷与特定突变和表型相关 可变性。前两个具体目标将使用电生理学技术来检查Cx32功能的丧失 由Cx32突变形式的门控和通透性改变引起。第三个特定目标将再次使用 电生理学技术评估Cx32突变可能导致该蛋白自杀的可能性 通道，导致表达它的细胞的功能中断。第四个具体目标是利用有针对性的 基因替换，以检测两种Cx32突变形式的差异效应。K02的支持 独立科学家奖将确保申请者能够在基础科学方面保持至少75%的努力 在进行研究的同时，还受益于新闻部独特的科学环境 阿尔伯特·爱因斯坦医学院的神经科学。这些因素将为继续 作为一名内科医生，在这个关键的早期发展阶段，PI的智力和技术发展- 从事翻译研究的独立项目的科学家。

X-linked Charcot Marie-Tooth Disease (CMTX) is an inherited peripheral neuropathy associated with mutations in the gap junction protein connexins 32 (Cx32). The central tenet of this proposal is that alterations in the functional properties of the ion channel formed by Cx32 can cause CMTX. Further, we propose that to understand the link between mutations and the disorder, we must explore the specific nature of the induced deficits in channel gating, permeability and control of formation. Although an association between a specific mutation in an ion channel and a neuromuscular disease is often compelling, the mechanism that underlies the deficit can remain unrevealed by clinical measures, morphologic examination or epidemiology. The studies )roposed in this grant are a direct and logical continuation of the applicant's previous work exploring the link )etween CMTX and the mutations in the genes controlling gap junction proteins; they build on previous efforts to correlate functional deficits at the cellular and subcellular level with specific mutations and with phenotypic variability. The first two specific aims will use electrophysiologic techniques to examine the loss of Cx32 function resulting from alterations in gating and permeability of mutant forms of Cx32. The third specific aim will again use electrophysiologic techniques to evaluate the possibility that mutations in Cx32 may turn this protein into a suicide channel, leading to disrupted function in cells in which it is expressed. The fourth specific aim utilizes targeted gene replacement to examine the differential effects of two mutant forms of Cx32. The support of a K02 Independent Scientist Award will insure that the applicant is able to maintain at least 75% effort in basic science research while at the same time benefiting from the unique scientific environment of the Department of Neuroscience of the Albert Einstein College of Medicine. These factors will provide an opportunity for continued intellectual and technical development of the PI during this critical early period of development as a physician- scientist engaged in an independent program of translational research.