BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR

描述(直接从应用程序中获取) 囊性纤维化(CF)由500多种不同的遗传病引起 编码囊性纤维化传导调节因子的基因突变， CFTR。在呼吸道和其他组织，如汗腺和胃肠道， CFTR被认为调节细胞内液体和电解质的运动 膜通过氯化物、水和/或三磷酸腺苷传导。最常见的 遗传的cftr突变通过破坏正常的加工过程而导致疾病 转而导致新合成蛋白质降解的途径 CFTR在细胞表面缺乏表达。最值得注意的是，突变 这会导致CFTR的降解，通常对蛋白质的影响很小 功能，提高了改善人口贩运的治疗方法的可能性 或者块降级可以在小区处提供足够的CFTR功能 表面防病。因此，CF研究的一个基本领域是 要了解正常的CFTR生物合成途径，请研究 突变影响生物发生，并开发针对 纠正这些缺陷。 CFTR与大多数其他复杂的整膜蛋白一样的生物发生 涉及新生链条的转移、折叠、分类和贩运 通过内质网(ER)。此过程在 通过内质网的转位机制和蛋白质伴侣逐步实现。 在拟议的工作中，野生型和突变型CFTR生物发生的事件将是 在无细胞和非洲爪哇卵母细胞表达系统中进行了系统研究。 这些研究的一个主要重点将是通过以下方式确定机制 哪些多肽区域易位并整合到脂类中 双层的。编码cftr特定区域的截短和嵌合载体 将被生成并用于开发随后的分析 初生链的拓扑成熟和早期组装事件。通过 将复杂的折叠过程分解为一系列不同的步骤，这些步骤 研究将实现理解分子的三个重要目标 本病的发病机制。首先，定义了CFTR拓扑事件 成熟和确定链中的决定因素，指导这些 事件。其次，他们确定了转位机制，通过这些机制 决定因素起作用，并将特定的装配功能分配给 那台机器。第三，他们将描述 正常的CFTR生物发生受到遗传突变的干扰。从这部作品中 将对CFTR的生物发生有一个详细的了解。身份识别 参与这一过程的特定细胞蛋白将提供新的 治疗CF和其他人类疾病的潜在靶点 蛋白质交易也牵涉其中。

DESCRIPTION (Taken directly from the application) Cystic Fibrosis (CF) is caused by more than 500 different inherited mutations in the gene encoding the cystic fibrosis conductance regulator, CFTR. In the airway and other tissues such as the sweat gland and GI tract, CFTR is believed to regulate fluid and electrolyte movement across the cell membrane via chloride, water, and/or ATP conduction. The most common inherited CFTR mutations cause disease by disrupting normal processing pathways which in turn results in degradation of newly synthesized protein and lack of CFTR expression at the cell surface. Most remarkably, mutations which result in CFTR degradation often have only minor effects on protein function, raising the possibility that therapies which improve trafficking or block degradation might provide adequate CFTR function at the cell surface to prevent disease. A fundamental area of CF research is therefore to understand normal CFTR biosynthetic pathways, investigate how different mutations affect biogenesis, and to develop treatments to aimed at correcting these defects. Biogenesis of CFTR like most other complex integral membrane proteins involves translocation, folding, sorting and trafficking of nascent chains through the endoplasmic reticulum (ER). This process is directed in a stepwise manner by translocation machinery and protein chaperones of the ER. In the proposed work, events of wild type and mutant CFTR biogenesis will be systematically examined in cell-free and Xenopus oocyte expression systems. A major focus of these studies will be aimed at identifying mechanisms by which peptide regions are translocated across and integrate into the lipid bilayer. Truncated and chimeric vectors encoding specific regions of CFTR will be generated and used to develop assays with which to follow topological maturation and early assembly events of the nascent chain. By dissecting complex folding processes into a series of distinct steps, these studies will accomplish three important goals in understanding the molecular pathogenesis of CF. First, they define events of CFTR topological maturation and identify determinants within the chain which direct these events. Second, they identify translocation machinery through which these determinants act and assign specific assembly functions to components of that machinery. And third they will characterize the mechanism by which normal CFTR biogenesis is disrupted by inherited mutations. From this work will emerge a detailed understanding of CFTR biogenesis. Identification of specific cellular proteins involved in this process will provide new potential targets for therapy of CF and other human diseases in which protein trafficking is involved.