PHYSIOLOGIC AND GENETIC STUDY OF LUNG DISEASE IN CF MODEL

肺部疾病是CF患者发病的主要原因和死亡的主要原因。肺部疾病的特征在于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。然而，CF相关肺病的严重程度是可变的，CFTR基因型相同的患者中的疾病，以及单卵CF双胞胎与双卵CF双胞胎相比的较高一致性，表明非CFTR遗传因素在疾病中的作用。这些次级遗传因素的鉴定将拓宽我们对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，通过人类研究描绘CF肺病的遗传影响是不可行的。CFTR功能缺陷的小鼠“CF小鼠”通常在5周龄时死于肠梗阻，而没有显示出显著的肺部疾病。然而，通过断奶到流质饮食来改善肠梗阻，导致寿命增加和随之而来的异常肺表型的披露。特别是，同类C57 BL/6 J（B6）CF小鼠，在没有病原体的情况下，自发地出现炎性肺病的体征，与CF患者中所见的那些没有什么不同。相比之下，在相同条件下，在其对照亚种或其他品系的F小鼠中未观察到肺部疾病的迹象，包括BALB/cJ（Bc）同类CF动物。因此，CF小鼠的两个同源品系提供了表征导致CF肺病的因素以及映射和表征差异背后的次级遗传因素的手段。拟定的研究将采用肺环境中性粒细胞功能的深入生理学表征，沿着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小鼠之间肺表型差异的因素，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.