MOLECULAR PHENOTYPES OF CYSTIC FIBROSIS

描述（直接从应用程序中获取） 研究SCOR应用的专门中心是了解 囊性癌基因突变的临床生物学和生化后果 纤维化跨膜传导调节因子（CFTR）， 囊性纤维化（CF）。 该计划汇集了科学家和 具有广泛专业知识的临床医生来分析突变体的影响 CFTR的功能是从疾病患者对细胞的影响到 蛋白质结构的变化。 扩大图片的 CF的表型范围强调了CFTR在 上皮组织 特定组织的缺陷以及 不同分子导致的疾病的一般表现 缺陷对治疗策略的设计有影响， 参见 SCOR分为四个研究项目（RP），两个试点项目， (PP)和三个核心单位，分为三个研究领域。 在 第一个区域，RP 1将定义表型表达谱， CFTR突变和相关表型差异的患者， 疾病表达与CFTR中的特定突变有关。 除了 具有典型CF表现的患者，本研究的具体目的 项目将描述具有非典型表现的患者， 不同基因型类别中表型的范围和严重程度， 将突变与各种表型相关联。第二个研究领域 在细胞水平上处理CFTR功能。 生物物理特性 从患者研究中定义的CFTR的各种突变形式 将在RP 2中使用复溶的纯化蛋白进行研究 脂质双层;目标是确定调节的性质， 通过ATP结合或水解测定野生型和突变型CFTR， CFTR分子之间是否发生相互作用。 RP 3将解剖 通过检查突变体在上皮细胞中CFTR的细胞内加工 似乎被阻止传递到顶膜。 具体重点 将研究胰腺功能不全患者中的突变蛋白 已知症状较轻 PP 1将开发一种新的方法， 分析CFTR在细胞内膜中的功能。 第三区域 调查将是区域（域）的结构分析， 使用生物物理方法的CFTR。 RP 4将使用圆二色性（CD）来 研究野生型跨膜结构域的结构与功能关系 型和各种突变形式的CFTR。 PP 2将定义 第一个核苷酸结合折叠和R结构域， 在细菌中过度表达。 这些将用于结构 使用核磁共振光谱比较野生型 和突变体 除了管理核心，CF患者 数据库和蛋白质和表达核心将用于支持 以上项目。 SCOR的结果应有助于深入了解 CF病理学的分子机制，并应提供建议， 改善治疗方法。

DESCRIPTION (Taken directly from the application) The goal of this specialized center of research SCOR application is to understand the clinical biological and biochemical consequences of mutationsin the cystic fibrosis transmembrane conductance regulator (CFTR), the gene defective in cystic fibrosis (CF). The program brings together scientists and clinicians with a broad range of expertise to analyze the effects of mutant CFTR function from the disease in patients to the effects on cells to the changes in the structure of the protein. The broadening picture of the phenotypic range of CF emphasizes the vital role that CFTR plays in epithelial tissues. The deficiencies in specific tissues as well as the general manifestations of the disease resulting from different molecular defects have implications for the design of therapeutic strategies to treat CF. The SCOR is organized into four Research Projects (RP), two Pilot Projects (PP), and three Core Units, grouped into three research areas. In the first area, RP1 will define the spectrum of phenotypic expression in patients with CFTR mutations and correlate phenotypic differences in disease expression with specific mutations in CFTR. In addition to patients with typical manifestations of CF, the specific aims of this project will characterize patients with atypical manifestations define the range andseverity of phenotypes in different genotype classes and correlate mutations to the various phenotypes. The second area of research deals with CFTR function at the cellular level. The biophysical properties of the various mutant forms of CFTR as defined from the patient studies will be studied in RP2 with the use of purified protein in reconstituted lipid bilayers; the goals are to define the nature of the regulation of the wild type and mutant CFTRs by ATP binding or hydrolysis and to determine whether interaction occurs between CFTR molecules. RP3 will dissect the intracellular processing of CFTR in epithelial cells by examiningmutants that appear blocked from delivery to the apical membrane. A specific focus will be the study of mutant proteins seen in pancreatic sufficient patients known to have milder symptoms. PP1 will develop anovel method for analyzing the function of CFTR in intracellular membranes. The third area of investigation will be the structural analysis of regions (domains) of CFTR using biophysical methods. RP4 will use circular dichroism (CD) to study structure function relationships in the transmembrane domains of wild type and various mutant forms of CFTR. PP2 will define regions of the first nucleotide binding fold and the R domain that allow soluble over-expression in bacteria. These will then be used for structural studies using nuclear magnetic resonance spectroscopy to compare wild type and mutant forms. In addition to the Administration Core, theCF patient database and the Protein and Expression Core will serve to support the above projects. The results from SCOR should lead to insights into the molecular mechanisms of CF pathology and should provide suggestions for improved therapeutic approaches.