MOLECULAR PHENOTYPES OF CYSTIC FIBROSIS

囊性纤维化的分子表型

• 批准号: 2770481
• 负责人: LAP-CHEE TSUI
• 金额: $ 57.78万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770481
• 关键词: chloride channels; cystic fibrosis; gene mutation; molecular pathology; phenotype

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.

描述（直接从应用程序中获取）目标 专业研究中心SCOR应用程序是了解 突变的临床生物学和生化后果在囊性中 纤维化跨膜电导调节剂（CFTR），基因缺陷 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可以分析突变体的影响 患者疾病的CFTR功能到对细胞影响到细胞的影响 蛋白质结构的变化。 宽广的图片 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组织为四个研究项目（RP），这是两个试点项目 （PP）和三个核心单元分为三个研究领域。 在 第一个区域，RP1将定义表型表达的频谱 患有CFTR突变并相关的表型差异的患者 CFTR中具有特异性突变的疾病表达。 此外 CF典型表现的患者，这是特定目的 项目将表征非典型表现的患者定义 在不同基因型类别中表型的范围和性 与各种表型相关的突变。第二个研究领域 在细胞水平上处理CFTR功能。 生物物理特性 由患者研究定义的各种突变形式的CFTR 将在RP2中使用纯化的蛋白质在重构中进行研究 脂质双层；目标是定义监管的性质 通过ATP结合或水解，野生型和突变CFTR，并确定 CFTR分子之间是否发生相互作用。 RP3将剖析 通过检查蒸气剂，CFTR的细胞内加工在上皮细胞中 从递送到根尖膜的情况似乎被阻塞。 一个特定的重点 将是对胰腺足够患者中突变蛋白的研究 已知有温和的症状。 PP1将开发用于 分析CFTR在细胞内膜中的功能。 第三个区域 调查将是对区域（域）的结构分析 CFTR使用生物物理方法。 RP4将使用圆二色性（CD） 野生跨膜结构域中的研究结构功能关系 类型和各种突变形式的CFTR。 PP2将定义 首先核苷酸结合褶皱和R结构域，允许可溶性 细菌中的过表达。 然后这些将用于结构 使用核磁共振光谱进行比较野生型的研究 和突变形式。 除了管理核心，THECF患者 数据库以及蛋白质和表达核心将有助于支持 上述项目。 SCOR的结果应导致对 CF病理的分子机制，应为 改进的治疗方法。