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

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）：连接蛋白是形成间隙连接通道的完整膜蛋白。然而，最近的数据表明，连接蛋白可能具有以下作用：1)调节细胞生长和增殖；2)抗凋亡和坏死细胞死亡；3)独立于功能性通道形成的转录调控。人类连接蛋白47 （CX47）的突变导致Pelizaeus Merzbacher样疾病（PMLD），一种严重的疾病，或一种较轻的遗传性痉挛性麻痹（HSP）表型。然而，这些突变引起人类疾病的细胞机制和它们不同影响的基础都没有得到很好的理解。由于预测PMLD和HSP突变体都不能形成功能正常的连接通路，我们提出PMLD突变引起的更严重的疾病不是基于连接偶联的丧失。相反，我们假设这种差异与一种独立于功能通道形成的机制有关。我们建议使用Illumina Beadchip技术来评估和比较WT CX47或PMLD/HSP突变体在CX47敲除小鼠原代培养的少突胶质细胞中表达时产生的基因表达模式。当导致疾病的CX47突变体在缺乏CX47WT的少突胶质细胞中表达时，这将允许识别细胞通路中断。我们将特别关注UPR激活或连接复合体解体的转录后遗症。本文提出的实验应提供以下认识：1)PMLD和HSP的发病机制；2)这两种疾病之间差异的基础。虽然不是本研究的主要目的，但这些研究也可能为了解Cx47WT在少突胶质细胞中的作用以及其他连接蛋白突变引起的人类疾病的发病机制提供线索。