MOLECULAR PHENOTYPES OF CYSTIC FIBROSIS

描述(直接取自应用程序)这一目标 专业研究中心的SCOR应用是为了了解 囊性变的临床、生物学和生化后果 肝纤维化跨膜传导调节因子(CFTR)基因缺陷的研究 囊性纤维化(CF)。该项目汇集了科学家和 临床医生具有广泛的专业知识来分析突变的影响 CFTR的功能从疾病对患者细胞的影响到对 蛋白质结构的变化。不断扩大的图景 Cf的表型范围强调了CFtr在 上皮组织。特定组织中的缺陷以及 由不同分子引起的疾病的一般表现 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，RP1将定义在 CFTR突变和相关表型差异的患者 Cftr基因特定突变的疾病表达。除了……之外 具有典型临床表现的患者，其治疗的具体目的 该项目将以非典型表现的患者为特征，定义 不同类型和类型的表型的范围和严重性 突变与各种表型相关。第二个研究领域 在细胞水平上处理CFTR的功能。生物物理特性 根据患者研究定义的各种CFTR型突变形式 将在RP2中使用重组的纯化蛋白进行研究 脂质双分子层；目标是定义调节的性质 野生型和突变型CFTRs通过三磷酸腺苷结合或水解法测定 CFTR分子之间是否发生相互作用。RP3将剖析 通过检测突变体在上皮细胞中对CFTR的胞内处理 它们似乎无法输送到根尖膜上。一个特定的焦点 将对胰腺充足患者的突变蛋白进行研究 已知症状较轻。PP1将开发一种新的方法来 分析CFTR在细胞内膜中的功能。第三个领域 调查的内容将是对以下区域(域)的结构分析 使用生物物理方法的CFTR。RP4将使用圆二色(CD)来 野生型细胞跨膜区结构与功能关系的研究 Cftr的类型和各种突变形式。PP2将定义 第一个核苷酸结合折叠和允许溶解的R结构域 在细菌中过度表达。然后，这些将用于结构 利用核磁共振波谱比较野生型的研究 和变种形式。除了管理核心，CF患者 数据库以及蛋白质和表达核心将用于支持 以上项目。SCOR的结果应该会让我们深入了解 CF病理的分子机制，应为临床治疗提供参考 改进治疗方法。

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.