PHYSIOLOGIC AND GENETIC STUDY OF LUNG DISEASE IN CF MODEL

肺部疾病是CF患者发病率的主要贡献者和死亡的主要原因。肺部疾病的特点是慢性炎症和机会性病原体定植引起的肺梗阻和组织损伤。然而，与CF相关的肺部疾病的严重程度是不同的，并且具有相同CFTR基因的患者中的疾病，以及与同卵双生的CF双胞胎相比，单合子患者的一致性更高，这表明非CFTR遗传因素在疾病中的贡献。这些次级遗传因素的识别将拓宽我们对CF病的认识，并可能导致新的治疗方法。然而，由于环境变异性、遗传异质性和样本量小，通过人类研究来描述遗传对CF肺病的影响是不可行的。CFTR功能缺陷的小鼠“CF小鼠”通常在5周大时死于肠梗阻，没有表现出明显的肺部疾病。然而，通过流质饮食来改善肠梗阻会导致寿命延长，并因此暴露出异常的肺表型。特别是，同基因的C57BL/6J(B6)CF小鼠，在没有病原体的情况下，会自发地发展成炎症性肺部疾病的迹象，这与在CF患者中看到的情况没有什么不同。相反，在相同的条件下，在它们的对照亚种或其他品系的F小鼠中，包括BALB/CJ(BC)同源的CF动物，没有观察到肺部疾病的迹象。因此，这两个同源品系的CF小鼠提供了一种手段来表征导致CF肺部疾病的因素，以及定位和表征潜在差异的次要遗传因素。这项拟议的研究将采用深入的肺环境中性粒细胞功能的生理学特征，以及对照育种实验和候选基因和QTL遗传作图，以确定导致B6和BC CF小鼠肺表型差异的因素，以及可能的CF患者变异性。

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.