GENE MODIFIERS OF CYSTIC FIBROSIS LUNG DISEASE

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。遗传性疾病囊性纤维化，CF，是由囊性纤维化跨膜传导调节因子（CFTR）的部分或完全功能丧失引起的。CFTR的功能尚不完全清楚，尽管人们一致认为其主要功能是作为上皮细胞中的顶端氯离子通道。作为一种临床疾病，CF显示出许多不同的特征，包括肺部疾病，CF死亡的主要原因。CF气道的特征在于一长串属性，包括增稠的分泌物、各种细菌物种的慢性定植、过度炎症和蛋白酶负荷以及鲁米那钠的过度吸收，仅举几例。不仅很难看出氯离子通道功能的改变如何导致这种复杂的表型，其他导致病理生理学的事件也不清楚。作为一种方法，以确定过程中的病理生理学，我们已经筛选了3组CF患者的一个大面板的基因组变异。选择这些基因是因为它们的产物在CF发病机制中被认为是重要的途径中，或者已被证明与其他肺部疾病（例如哮喘）相关。这项研究不仅限于肺部疾病，还收集了关于生长和营养状况、胎粪性肠梗阻和CF相关糖尿病的有限数据。因此，参与生长、肥胖、I型和II型糖尿病等的内分泌调节的基因也被添加到候选修饰物的列表中。本研究的目的是通过确认相关性来补充现有的研究，并开始阐明它们修饰CF表型的机制。因此，一个项目的目标将是收集第二组患者，可以在其上测试修饰物关联，并收集与显示关联的表型相关的额外数据。这项研究还将建议收集先证者及其父母，以便进行其他类型的分析，如传播不平衡检验。人类基因组单倍型绘图的进展也应该允许更有效地分析单倍型分布。此外，我们将跟踪观察TGF β 1通路（TGF β 1，TGF β R 3和MADH 3）的变异与CF患者之间肺功能的差异相关。TGF β 1途径是复杂的，几乎在每种细胞类型中表达，并影响CF的各种感兴趣的过程。另一个项目将跟踪观察内皮素受体A（EDNRA）和β 2-肾上腺素能受体（ADRB 2）的变体，这些基因影响平滑肌收缩，与CF患者的生存有关。在两个患者队列中观察到ADRB 2相关性，因此本项目将重点了解这些变体对患者结局产生影响的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The genetic disease cystic fibrosis, CF, is caused by partial or complete loss of function of the cystic fibrosis transmembrance conductance regulator (CFTR). The function of CFTR is not entirely clear, although it is agreed that a major function is as an apical chloride channel in epithelial cells. As a clinical disorder, CF displays numerous distinct features, including pulmonary disease, the predominant cause of CF mortality. The CF airway is characterized by a long list of attributes, including thickened secretions, chronic colonization by various bacterial species, excessive inflammation and protease burden, and hyperabsorption of luminal sodium, just to name a few. Not only is it difficult to see how altered chloride channel function can lead to this complex phenotype, other events contribuitng to the pathophysiology are not clear either. As a method to identify processes contributing to the pathophysiology, we have screened a population of 3 groups of CF patients for genomic variants of a large panel of genes. These genes were selected because their products are in pathways suggested to be important in CF pathogenesis or have been shown to associate with other pulmonary diseases (asthma, for example). The study expanded beyond just pulmonary disease, and limited data on growth and nutritional status, meconium ileus, and CF-related diabetes were collected as well. Accordingly, genes involved in the endocrine reguation of growth, obesity, type I and II diabetes, etc. were added to the list of candidate modifiers as well. The goal of this study is to complement an existing study by confirming associations and to begin to elucidate the mechanism by which they modify CF phenotypes. As such, the goal of one project will be to collect a second cohort of patients on which the modifier associations can be tested and to collect additional data relevant to the phenotypes showing assocaitons. This study will also propose to collect probands and their parents so that additional types of analyses can be carried out, such as transmission disequilibrium tests. Progress in haplotype mapping of the human genome should also allow more efficient analyses of haplotype distributions as well. Also, we will follow up the observation that variants in the TGFb1 pathway (TGFb1, TGFBR3 and MADH3) associate with differences in pulmonary function between CF patients. The TGFb1 pathway is complex, expressed in virtually every cell type and affecting a variety of processes of interest to CF. Another project will follow up on the observation that variants of endothelin receptor A (EDNRA) and beta 2-adrenergic receptor (ADRB2), genes that affect smooth muscle contraction, associate with survival of CF patients. The ADRB2 association has been seen in two cohorts of patients and thus this project will focus on understanding the mechanism by which the variants exert their effects on patient outcome.