MOLECULAR BASIS OF THE CYSTIC FIBROSIS PHENOTYPE

囊性纤维化表型的分子基础

• 批准号: 6380943
• 负责人: LAP-CHEE TSUI
• 金额: $ 60.25万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380943
• 关键词: chloride channels; cystic fibrosis; gene mutation; molecular pathology; phenotype

The goal of this SCOR application is to understand the clinical, biological and biochemical consequences of mutations in CFTR, the gene defective in cystic fibrosis (CF). The program brings together a group of basic scientists and clinician researchers with a broad range of expertise to the common task of analyzing the CF disease from different angles, through studying the CFTR molecular defects in patients, generating, mouse models, mapping of modifier genes, and using cell culture and in vitro systems for the protein. We combine our strengths in the area of CF patient documentation, human and mouse genetics, biochemistry and cell biology. The SCOR is organized into 4 Research Projects (RP), 3 Pilot Projects (PP) and 3 Core Units, grouped into 3 research areas, namely, clinical and genetic studies of patients, mouse models of identification of CF modifier genes, and direct characterization of CFTR. In the first area, RP1 will establish a comprehensive understanding of the spectrum of CF disease phenotype caused by or associated with the primary and secondary genetic determinants of the disease. In the second, RP2 will study the role of ClC-2 chloride channels in mediating epithelial chloride secretion in a mouse model and RP3 will dissect the physiologic and genetic aspects of lung disease in CF mice of a specific genetic background. In addition, a pilot project, PP3, is included to characterize the liver disease recently observed in one of the congenic CF mouse strains. These studies will discover new pathways through which alternative methods may be devised to treat CF. In the third area, RP4 will pursue a detailed analysis at the molecular, cellular and functional levels to establish the consequences of the missense mutations that occur in the first nucleotide binding domain (NBD1) of CFTR and mutations causing carboxyl terminal truncations will be used as probes for these studies. This will be complemented by the two pilot projects: PP1 which will explore a new fluorescence transfer technique for the study of transmembrane segment interactions and PP2 which will examine if purified CFTR an mediate energy-dependent transport of large organic anions such as glutamate and glutathione in a reconstituted system. In addition to the Administration Core, the Patient/Biostatistics Core, and the Mouse Core will serve to support the hove projects. The results from Score should yield novel insights into the molecular mechanisms of CF pathology and should lead to new improved therapeutic approaches.

该 SCOR 应用的目标是了解 CFTR（囊性纤维化 (CF) 的基因缺陷）突变的临床、生物学和生化后果。该项目汇集了一批具有广泛专业知识的基础科学家和临床研究人员，通过研究患者的 CFTR 分子缺陷、生成小鼠模型、修饰基因图谱，从不同角度分析 CF 疾病的共同任务，并使用细胞培养物和体外系统来获得蛋白质。我们结合了 CF 患者记录、人类和小鼠遗传学、生物化学和细胞生物学领域的优势。 SCOR 分为 4 个研究项目 (RP)、3 个试点项目 (PP) 和 3 个核心单元，分为 3 个研究领域，即患者的临床和遗传学研究、CF 修饰基因鉴定的小鼠模型以及直接表征的CFTR。 在第一个领域，RP1 将全面了解由疾病的主要和次要遗传决定因素引起或与之相关的 CF 疾病表型谱。在第二部分中，RP2 将研究 ClC-2 氯通道在小鼠模型中介导上皮氯分泌中的作用，RP3 将剖析特定遗传背景的 CF 小鼠肺部疾病的生理和遗传方面。此外，还包括一个试点项目 PP3，用于表征最近在一种同源 CF 小鼠品系中观察到的肝脏疾病。这些研究将发现新的途径，通过这些途径可以设计出治疗 CF 的替代方法。在第三个领域，RP4将在分子、细胞和功能水平上进行详细分析，以确定CFTR第一个核苷酸结合域（NBD1）中发生的错义突变的后果，并且导致羧基末端截断的突变将被用作对这些研究进行探索。这将得到两个试点项目的补充：PP1 将探索一种新的荧光转移技术，用于研究跨膜片段相互作用；PP2 将检查纯化的 CFTR 是否介导大有机阴离子（如谷氨酸和谷胱甘肽）的能量依赖性运输。重构的系统。除了管理核心之外，患者/生物统计核心和鼠标核心也将用于支持 hove 项目。 Score 的结果应该会对 CF 病理学的分子机制产生新的见解，并应该导致新的改进的治疗方法。