Pathogenesis of Disease-Associated Connexin-31 Mutations

疾病相关的 Connexin-31 突变的发病机制

• 批准号: 7247108
• 负责人: ZHUOHUA ZHANG
• 金额: $ 32.96万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247108
• 关键词: Adult; Apoptotic; Cell Communication; Cell Death; Cell Line; Cells; Charcot-Marie-Tooth Disease; Connexins; Defect; Development; Disease; Disruption; Gap Junctions; Genes; Hearing; Homeostasis; Human; Inherited; Inner Hair Cells; Maintenance; Mediating; Molecular; Molecular Chaperones; Molecular Conformation; Molecular Weight; Mus; Mutation; Numbers; Organ; Organ of Corti; Outer Hair Cells; Pathogenesis; Pathology; Patients; Peripheral Nervous System Diseases; Process; Proteins; Research; Role; Signal Transduction; Stress; Testing; Transgenic Mice; Transgenic Organisms; base; connexin-31; design; hearing impairment; in vivo; intercellular communication; loss of function; mouse model; mutant; response; skin disorder; spiral ganglion; trafficking

DESCRIPTION (provided by applicant): Gap junctions, assembled by connexins, mediate cell-cell communication and maintain cellular homeostasis. In human, mutations in genes encoding connexins are identified in a number of inherited diseases. Mutations in connexin-31 are associated with hearing impairment, erythrokeratodermia variabilis (EKV), and peripheral neuropathy. Little is known about the molecular basis for the distinct pathogenic processes associated with Cx31 mutants. In preliminary study, we have shown the expression of Cx31 in adult organ of corti. We also found that hearing impairment-associated Cx31 mutants show impaired channel function, loss of assembly at cell-cell contacts, and defective intracellular trafficking. Notably, EKV-associated Cx31 mutants promote apoptotic cell death, in addition to the defects found in hearing impairment-associated mutants. Moreover, expression of disease associated Cx31 mutants induces BiP expression. We hypothesize that Cx31 mutant-associated hearing impairment and skin disease are consequences of abnormal intracellular trafficking of mutant proteins. The trafficking defect of the mutant proteins results from UPR induced by abnormal conformation of mutant proteins. In this proposal we propose: Specific aim 1. To define the intracellular trafficking defects of disease associated Cx31 mutants. Specific aim 2. To determine the molecular mechanism of cell death caused by expressing EKV-associated Cx31 mutants. Specific aim 3. To define the pathogenic mechanisms of disease-associated Cx31 mutants in vivo using transgenic mouse models. The results will facilitate both the understanding of the pathological mechanisms of Cx31 mutations and the design of potential treatments of these diseases.

描述（由申请人提供）：间隙连接由连接蛋白组装而成，介导细胞间通讯并维持细胞稳态。在人类中，在许多遗传性疾病中发现了编码连接蛋白的基因突变。 Connexin-31 突变与听力障碍、变异性红斑角化症 (EKV) 和周围神经病变有关。对于与 Cx31 突变体相关的独特致病过程的分子基础知之甚少。 在初步研究中，我们显示了Cx31在成人皮质器官中的表达。我们还发现，与听力障碍相关的 Cx31 突变体表现出通道功能受损、细胞间接触组装缺失以及细胞内运输缺陷。值得注意的是，除了听力障碍相关突变体中发现的缺陷之外，EKV 相关 Cx31 突变体还会促进细胞凋亡。此外，疾病相关的 Cx31 突变体的表达诱导 BiP 表达。我们假设 Cx31 突变相关的听力障碍和皮肤病是突变蛋白细胞内异常运输的结果。突变蛋白的运输缺陷是由突变蛋白的异常构象诱导的UPR造成的。 在此提案中，我们提出： 具体目标 1. 定义疾病相关 Cx31 突变体的细胞内运输缺陷。具体目标2.确定表达EKV相关Cx31突变体引起细胞死亡的分子机制。具体目标 3. 使用转基因小鼠模型确定疾病相关 Cx31 突变体的体内致病机制。 这些结果将有助于了解 Cx31 突变的病理机制以及这些疾病的潜在治疗方法的设计。