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.

肺病是发病率的主要因素，是CF患者死亡率的主要原因。肺部疾病的特征是由于慢性炎症和机会性病原体定植引起的肺阻塞和组织损伤。与Dizygotic CF双胞胎相比，与CFTR基因型相同的患者中，与CF相关的肺疾病的严重程度是可变的，并且单粒相比具有更高的一致性，而单氮的一致性更高，这表明该疾病中非CFTR遗传因素的贡献。这些次要遗传因素的识别将扩大我们对CF疾病的理解，并可能导致新的治疗方法。然而，由于环境变异性，遗传异质性和小样本量，通过人类研究，遗传对CF肺部疾病的影响是不可行的。缺乏CFTR功能“ CF小鼠”的小鼠通常会在5周龄的情况下死于肠道阻塞，而不会表现出明显的肺部疾病。然而，通过断奶到液体饮食上，改善肠道障碍物，导致寿命增加和肺部异常表型的结果披露。尤其是，在没有病原体的情况下，先天性的C57BL/6J（B6）CF小鼠会自发发展炎症性肺部疾病的迹象，这与CF患者中所见。相比之下，在相同的条件下，在其对照组或其他F小鼠（包括BALB/CJ（BC）ENCENIC CF动物）中未观察到肺部疾病的迹象。因此，CF小鼠的两种先天性菌株提供了一种表征造成CF肺部疾病的因素的手段，以及地图以及表征差异差异的次要遗传因素。拟议的研究将采用肺部环境中性粒细胞功能的深入生理表征，以及受控的育种实验以及候选基因和QTL遗传学映射，以确定导致B6和BC CF小鼠之间肺表型差异的因素，以及可能的CF患者可变性。