Pathogenesis of connexin 47 associated diseases

连接蛋白47相关疾病的发病机制

• 批准号: 7774254
• 负责人: CHARLES K ABRAMS
• 金额: $ 7.91万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774254
• 关键词: Apoptotic; Attention; Binding; Bioinformatics; Biometry; Cell Death; Central Nervous System Diseases; Collaborations; Complex; Connexins; Coupling; Data; Disease; Gene Cluster; Gene Expression; Genes; Goals; Growth; Hereditary Spastic Paraparesis; Human; Institutes; Integral Membrane Protein; Knockout Mice; Lead; Mutation; Necrosis; Oligodendroglia; Pathogenesis; Pathway interactions; Pattern; Pelizaeus-Merzbacher Disease; Phenotype; Proteins; Quantitative Reverse Transcriptase PCR; Resistance; Role; Severity of illness; Technology; Transcriptional Regulation; base; cell growth regulation; disease-causing mutation; gap junction channel; human disease; insight; intercellular communication; mutant; public health relevance; research study; response; Apoptotic; Attention; Binding; Bioinformatics; Biometry; Cell Death; Central Nervous System Diseases; Collaborations; Complex; Connexins; Coupling; Data; Disease; Gene Cluster; Gene Expression; Genes; Goals; Growth; Hereditary Spastic Paraparesis; Human; Institutes; Integral Membrane Protein; Knockout Mice; Lead; Mutation; Necrosis; Oligodendroglia; Pathogenesis; Pathway interactions; Pattern; Pelizaeus-Merzbacher Disease; Phenotype; Proteins; Quantitative Reverse Transcriptase PCR; Resistance; Role; Severity of illness; Technology; Transcriptional Regulation; base; cell growth regulation; disease-causing mutation; gap junction channel; human disease; insight; intercellular communication; mutant; public health relevance; research study; response

DESCRIPTION (provided by applicant): The connexins are integral membrane proteins that form gap junction channels. However, recent data suggest that connexins may have roles in: 1) regulation of cell growth and proliferation; 2) resistance to both apoptotic and necrotic cell death; and 3) regulation of transcription, which are independent of functional channel formation. Mutations in human connexin 47 (CX47) lead to either Pelizaeus Merzbacher Like Disease (PMLD), a severe disorder, or a milder Hereditary Spastic Paraparesis (HSP) phenotype. However, neither the cellular mechanisms by which these mutations cause human disease nor the bases for their differing effects are well understood. Because both PMLD and HSP mutants are predicted to be incompetent to form a functioning junctional pathway, we propose that the greater severity of disease caused by PMLD mutations is not based on loss of junctional coupling. Rather, we hypothesize that the difference is related to a mechanism independent of functional channel formation. We propose to use Illumina Beadchip technology to evaluate and compare the patterns of gene expression produced when WT CX47 or PMLD/HSP mutants are expressed in oligodendrocytes in primary culture obtained from the Cx47 knockout mice. This will allow for the identification of cellular pathways disrupted when disease causing CX47 mutants are expressed in oligodendrocytes lacking CX47WT. We will pay particular attention to transcriptional sequelae of activation of the UPR or disorganization of the junctional complex. The experiments proposed here should provide an understanding of 1) the pathogenesis of PMLD and HSP; and 2) the basis for the differences between these two disorders. Though not the primary goals of this proposal, these studies may also provide insight into the roles of Cx47WT in oligodendrocytes and mechanisms of pathogenesis of human diseases caused by mutations in other connexins. PUBLIC HEALTH RELEVANCE: Connexins are gap junction proteins which provide for intercellular communication, but may have other roles as well. This proposal studies the effects of mutations in a connexin gene which lead to disease of the central nervous system. These studies should lead to a better general understanding of how mutations in connexin genes lead to human disease.

描述（由申请人提供）：连接素是形成间隙连接通道的整体膜蛋白。但是，最近的数据表明连接素可能在：1）调节细胞生长和增殖中； 2）对凋亡和坏死细胞死亡的抗性； 3）转录的调节，这些转录与功能通道的形成无关。人连接47（CX47）中的突变导致Pelizaeus Merzbacher疾病（PMLD），严重的疾病或温和的遗传性痉挛性瘫痪（HSP）表型。但是，这些突变引起人类疾病的细胞机制和碱的不同作用都不是众所周知的。由于预测PMLD和HSP突变体均无法形成运行的连接途径，因此我们认为，PMLD突变引起的疾病的较高严重程度不是基于连接耦合的丧失。相反，我们假设差异与独立于功能通道形成的机制有关。我们建议使用Illumina Beadchip技术评估和比较当WT CX47或PMLD/HSP突变体在从CX47敲除小鼠中获得的原代培养物中表达时产生的基因表达模式。这将允许识别当缺乏CX47WT的少突胶质细胞中表达引起CX47突变体的疾病时，鉴定出破坏的细胞途径。我们将特别注意连接络合物的UPR激活或混乱的转录后遗症。这里提出的实验应提供对1）PMLD和HSP的发病机理的理解； 2）这两种疾病之间差异的基础。尽管这不是该提案的主要目标，但这些研究也可能提供对CX47WT在少突胶质细胞中的作用和人类疾病发病机理的作用，由其他连接素突变引起的。 公共卫生相关性：连接蛋白是间隙连接蛋白，可提供细胞间交流，但也可能具有其他角色。该建议研究了连接素基因中突变的影响，从而导致中枢神经系统疾病。这些研究应该使人们对连接蛋白基因突变如何导致人类疾病有更好的一般了解。