Connexin 32 Mutations in X-Linked CMT

X 连锁 CMT 中的连接蛋白 32 突变

• 批准号: 6857380
• 负责人: CHARLES K ABRAMS
• 金额: $ 17.43万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857380
• 关键词: Schwann cells; Xenopus; Xenopus oocyte; acidity /alkalinity; chimeric proteins; electrophysiology; gap junctions; gene mutation; genetically modified animals; hereditary motor and sensory neuropathy; ion transport; laboratory mouse; membrane channels; membrane permeability; membrane proteins; molecular pathology; protein structure function; sex linked trait; transfection; voltage gated channel

DESCRIPTION (provided by applicant): 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 proposed in this application are a direct and logical continuation of the applicant's previous work exploring the link between CMTX and the mutations in the genes controlling gap junction proteins; they build on previous efforts to correlate functional deficits at the cellular and sub-cellular 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.

描述（由申请人提供）：X连锁腓骨肌萎缩症（CMTX）是一种与间隙连接蛋白连接蛋白32（Cx32）突变相关的遗传性周围神经病。该提议的中心原则是 Cx32 形成的离子通道功能特性的改变可能导致 CMTX。此外，我们建议，为了了解突变与疾病之间的联系，我们必须探索通道门控、通透性和形成控制方面诱导缺陷的具体性质。尽管离子通道中的特定突变与神经肌肉疾病之间的关联通常令人信服，但临床测量、形态学检查或流行病学仍无法揭示缺陷背后的机制。本申请中提出的研究是申请人先前探索CMTX与控制间隙连接蛋白的基因突变之间联系的工作的直接且合乎逻辑的延续；他们建立在先前将细胞和亚细胞水平的功能缺陷与特定突变和表型变异相关联的努力的基础上。前两个具体目标将使用电生理学技术来检查由于 Cx32 突变体形式的门控和通透性改变而导致的 Cx32 功能丧失。第三个具体目标将再次使用电生理学技术来评估 Cx32 突变可能将该蛋白转变为自杀通道的可能性，从而导致其表达的细胞功能受损。第四个具体目标利用靶向基因替换来检查两种 Cx32 突变形式的差异效应。 K02独立科学家奖的支持将确保申请人能够在基础科学研究上保持至少75%的努力，同时受益于阿尔伯特·爱因斯坦医学院神经科学系独特的科学环境。这些因素将为 PI 作为从事独立转化研究项目的医师科学家在这一关键的早期发展阶段提供持续智力和技术发展的机会。