Connexin 32 Mutations in X-Linked CMT

X 连锁 CMT 中的连接蛋白 32 突变

• 批准号: 7569416
• 负责人: CHARLES K ABRAMS
• 金额: $ 14.93万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 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/7569416
• 关键词: Animal Model; Appearance; Basic Science; Biopsy; Calcium; Calcium Signaling; Cell membrane; Cells; Charcot-Marie-Tooth Disease; Chemicals; Clinical; Collaborations; Communication; Connexins; Coupled; Cyclic AMP; Cyclic Nucleotides; Development; Disease; Dyes; Environment; Epidemiology; Exercise; Fatigue; Gap Junctions; Genes; Grant; In Vitro; Independent Scientist Award; Inherited; Investigation; Ion Channel; Knock-in Mouse; Lead; Link; Liposomes; Measures; Mediating; Medicine; Membrane; Muscle Cramp; Mutation; Natural regeneration; Nature; Neuromuscular Diseases; Neurosciences; Pathology; Pathway interactions; Patients; Peripheral Nervous System Diseases; Permeability; Phenotype; Physicians; Predisposition; Property; Proteins; Research; Schwann Cells; Scientist; Second Messenger Systems; Severities; Signaling Molecule; Stimulus; Suicide; System; Techniques; Testing; Time; Translational Research; Work; Xenopus oocyte; college; connexin 32; cyclic-nucleotide gated ion channels; gene replacement; mutant; myelination; programs; reconstitution; research study; response; second messenger; voltage

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.

X连锁型charcot Marie Tooth病（CMTX）是一种与突变相关的遗传性周围神经病 在间隙连接蛋白连接蛋白32（CX32）中。该提议的中心宗旨是改变 CX32形成的离子通道的功能性能可能引起CMTX。此外，我们建议 了解突变与疾病之间的联系，我们必须探索诱导的特定性质 通道门控，渗透率和形成控制的缺陷。虽然特定之间的关联 离子通道中的突变和神经肌肉疾病通常是引人注目的，这种机制是基础的 通过临床措施，形态学检查或流行病学，赤字可能保持不变。研究 ）在这笔赠款中索取是申请人以前的工作的直接逻辑延续，探索了链接 ）在控制间隙连接蛋白的基因中的CMTX与突变之间；他们以先前的努力为基础 在细胞和亚细胞水平的功能缺陷与特定突变以及与表型相关 可变性。前两个具体目标将使用电生理技术来检查CX32功能的丧失 CX32突变形式的门控和渗透性的改变产生。第三个特定目标将再次使用 电生理技术评估CX32突变可能将这种蛋白变成自杀的可能性 通道，导致表达其表达的单元格的函数破坏。第四个特定目标利用了目标 基因替换以检查两种突变形式的Cx32的差异效应。 K02的支持 独立科学家奖将确保申请人能够在基础科学中保持至少75％的努力 研究同时受益于部门的独特科学环境 阿尔伯特·爱因斯坦医学院的神经科学。这些因素将为继续 PI的智力和技术发展在这一关键的早期发展时期，作为医生 - 科学家参与了转化研究的独立计划。