BIOGENESIS AND MOLECULAR PATHOGENESIS OF CFTR

描述（直接取自应用程序） 囊性纤维化（CF）是由500多种不同的遗传因素引起的。 编码囊性纤维化传导调节因子的基因突变， CFTR。 在气道和其他组织如汗腺和胃肠道中， CFTR被认为调节细胞内的液体和电解质运动 膜通过氯化物，水和/或ATP传导。 最常见的 遗传性CFTR突变通过破坏正常加工而引起疾病 这反过来又导致新合成的蛋白质降解的途径 以及在细胞表面缺乏CFTR表达。 最值得注意的是， 这导致CFTR降解往往只有轻微的影响蛋白质 功能，提高了改善贩运的治疗方法 或阻断降解可在细胞处提供足够的CFTR功能 表面，以防止疾病。 因此，CF研究的一个基本领域是 为了了解正常的CFTR生物合成途径， 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合膜蛋白一样的生物发生 涉及新生链的移位、折叠、分选和运输 通过内质网（ER）。 这个过程是在一个 通过内质网的转运机制和蛋白质伴侣以逐步的方式进行。 在所提出的工作中，野生型和突变型CFTR生物发生的事件将被研究。 在无细胞和非洲爪蟾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： 所述肽区域跨脂质易位并整合到脂质中 双层。 编码CFTR特定区域的截短和嵌合载体 将生成并用于开发检测方法， 拓扑成熟和新生链的早期组装事件。 通过 将复杂的折叠过程分解为一系列不同的步骤， 研究将实现三个重要目标，了解分子 CF的发病机制 首先，定义CFTR拓扑事件 成熟，并确定链内的决定因素，指导这些 事件 其次，他们确定了易位机制，通过这些机制， 决定因素起作用，并将特定的组装功能分配给 这个机器。 第三，他们将描述的机制， 正常的CFTR生物发生被遗传突变破坏。 从这项工作 将对CFTR的生物起源有详细的了解。 鉴定 参与这一过程的特定细胞蛋白质将提供新的 治疗CF和其他人类疾病的潜在靶点， 蛋白质的运输是有关系的。

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.