MOLECULAR PHENOTYPES OF CYSTIC FIBROSIS

囊性纤维化的分子表型

• 批准号: 2149686
• 负责人: LAP-CHEE TSUI
• 金额: $ 51.58万
• 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/2149686
• 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（直接取自应用程序）此目标 专业研究中心SCOR应用是为了了解 囊性囊肿突变的临床生物学和生化后果 纤维化跨膜电导调节因子（CFTR），该基因缺陷 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 CFTR功能从患者的疾病到对细胞的影响 蛋白质结构的变化。 扩大的图景 CF 的表型范围强调了 CFTR 在 上皮组织。 特定组织的缺陷以及 不同分子引起的疾病的一般表现 缺陷对设计治疗策略具有影响 CF。 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 将定义表型表达谱 CFTR 突变患者与表型差异相关 CFTR 中特定突变的疾病表达。 此外 具有典型 CF 表现的患者，本次治疗的具体目的 该项目将描述具有非典型表现的患者的特征，定义 不同基因型类别中表型的范围和严重程度以及 将突变与各种表型相关联。第二研究领域 涉及细胞水平的 CFTR 功能。 生物物理特性 根据患者研究定义的 CFTR 的各种突变形式 将在 RP2 中使用重构的纯化蛋白进行研究 脂质双层；目标是确定监管的性质 通过 ATP 结合或水解来测定野生型和突变型 CFTR CFTR分子之间是否发生相互作用。 RP3 将剖析 通过检查突变体进行上皮细胞 CFTR 的细胞内加工 似乎无法输送到顶膜。 特定的焦点 将研究在胰腺充足患者中观察到的突变蛋白 已知症状较轻。 PP1将开发一种新方法 分析 CFTR 在细胞内膜中的功能。 第三区 调查的重点是区域（领域）的结构分析 CFTR 使用生物物理方法。 RP4 将使用圆二色性 (CD) 研究野生动物跨膜域的结构功能关系 CFTR的类型和各种突变形式。 PP2 将定义区域 第一个核苷酸结合折叠和 R 结构域允许可溶 在细菌中过度表达。 然后这些将用于结构 使用核磁共振波谱法比较野生型的研究 和突变形式。 除了管理核心之外，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 的结果应该有助于深入了解 CF病理学的分子机制，并应提供建议 改进的治疗方法。