PHYSIOLOGIC AND GENETIC STUDY OF LUNG DISEASE IN CF MODEL

CF模型中肺部疾病的生理和遗传学研究

• 批准号: 6195625
• 负责人: LAP-CHEE TSUI
• 金额: $ 7.24万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6195625
• 关键词: animal breeding; chloride channels; cystic fibrosis; gene expression; genetic mapping; laboratory mouse; leukocyte activation /transformation; lung disorder; molecular cloning; molecular pathology; neutrophil; pathologic process; phenotype; quantitative trait loci

Lung disease is the major contributor to morbidity and the primary cause of mortality of CF patients. The lung disease is characterized by pulmonary obstruction and tissue damage due to chronic inflammation and opportunistic pathogen colonization. The severity of the CF-associated lung disease, how3ever, is variable, and disease among patients with identical CFTR genotypes, and a higher concordance in monozygotic compared to dizygotic CF twins, suggest the contribution of non-CFTR genetic factors in the disease. Identification of these secondary genetic factors will broaden our understanding of CF disease and possibly led to new treatments. The delineation of the genetic influences on CF lung disease, however, is not feasible through human studies due to environmental variability, genetic heterogeneity and small sample sizes. Mice deficient of CFTR function "CF mice" generally die of intestinal obstruction by the age of 5 weeks without displaying significant lung disease. Amelioration of the intestinal obstructions by weaning onto a liquid diet, however, results in increased lifespan and consequential disclosure of abnormal lung phenotypes. In particularly, congenic C57BL/6J (B6) CF mice, in the absence of pathogens, spontaneously develop signs of inflammatory lung disease, not unlike those seen in CF patients. In contrast, under the same conditions no sign of lung disease is observed in their control subs or other strains of F mice, including the BALB/cJ (Bc) congenic CF animals. The two congenic strains of CF mice thus provide a means to characterize the factors contributing to the CF lung disease as well as map and characterize secondary genetic factors underlying the differences. The proposed study will employ an in-depth physiological characterization of pulmonary milieu neutrophil function, along with controlled breeding experiments and candidate gene and QTL genetic mapping to identify the factors contributing to the differences in lung phenotypes between the B6 and Bc CF mice, and possibly CF patient variability.

肺部疾病是CF患者发病的主要原因和死亡的主要原因。肺部疾病的特征是慢性炎症和机会性病原体定植导致的肺部阻塞和组织损伤。然而，CF 相关肺病的严重程度是可变的，具有相同 CFTR 基因型的患者中的疾病以及同卵 CF 双胞胎中的一致性高于异卵 CF 双胞胎，表明非 CFTR 遗传因素在该疾病中的作用。这些次要遗传因素的鉴定将拓宽我们对 CF 疾病的理解，并可能带来新的治疗方法。然而，由于环境变异性、遗传异质性和小样本量，通过人体研究来描述遗传对 CF 肺病的影响是不可行的。缺乏CFTR功能的小鼠“CF小鼠”通常在5周龄时死于肠梗阻，而没有表现出明显的肺部疾病。然而，通过断奶改吃流质饮食来改善肠梗阻会导致寿命延长，并随之出现肺部异常表型。特别是，同源 C57BL/6J (B6) CF 小鼠在没有病原体的情况下，会自发出现炎症性肺部疾病的症状，与 CF 患者中看到的情况不同。相比之下，在相同条件下，在其对照亚种或其他 F 小鼠品系（包括 BALB/cJ (Bc) 同类 CF 动物）中没有观察到肺部疾病的迹象。因此，CF 小鼠的两种同源品系提供了一种表征导致 CF 肺病的因素以及绘制和表征差异背后的次要遗传因素的方法。拟议的研究将采用肺环境中性粒细胞功能的深入生理特征，以及受控育种实验以及候选基因和 QTL 遗传图谱，以确定导致 B6 和 Bc CF 小鼠之间肺表型差异的因素，并可能CF 患者的变异性。