SCOR IN AIRWAY BIOLOGY & PATHOGENESIS OF CYSTIC FIBROSIS

该SCOR的目的是了解气道的正常生物学 上皮细胞和囊性纤维化（CF）疾病的发病机制。的 CF中的分子缺陷是CFTR Cl通道功能的丧失， 导致有缺陷的跨上皮Cl转运。最近的研究 正常和CF气道都分泌具有抗菌活性的物质 在气道表面液体中。报告称CF表面液具有高NaCl 浓度可以解释CF和TIE中缺乏细菌杀灭 Cl通道分子效应的临床缺陷。在项目1中， Drs. Welsh和Ostedgaard将重点关注CFTR Cl通道的调节， R结构域的磷酸化。磷酸化是生理性的 控制通道活动的机制。他们的研究应该提供 详细的功能和三维结构信息， R结构域和CFTR调控的新见解。在项目4中，博士。 Zabner和Smith将重点关注气道表面液体盐的调节 通过CFTR Cl通道的浓度。将采用补充办法 为了在体外和体外测量人气道表面流体盐浓度， in vivo.纠正气道成分异常的新方法 还将研究表面流体。在项目2中，麦克雷博士和 塔克将研究人类β-防御素1和2（hBD-1）的生物学 和-2）。这些盐抑制防御素是抗微生物肽 在气道上皮中表达。他们的研究将决定细胞- 特定的定位，这个多样化的β-防御素基因家族。在项目 Engelhardt博士专注于气道的综合生理学。他 将专门研究粘膜下腺体对 气道防御机制该项目采用了一种新颖的研究方法 小鼠和气管异种移植物在存在和不存在亚- 粘膜腺所有的项目都依赖于细胞培养核心， 组织采集和CF气道相关模型的开发。 从本SCOR的综合方法中获得的见解将得到改善 我们对CF气道疾病发病机制的理解， 新疗法

The goal of this SCOR is to understand the normal biology of airway epithelia and the pathogenesis of disease in cystic fibrosis (CF). The molecular defect in CF is the loss of CFTR Cl channel function, which results in defective transepithelial Cl transport. Recent studies that both normal and CF airway secrete substances with antibacterial activity in the airway surface fluid. Reports that CF surface fluid has a high NaCl concentration would explain the lack of bacterial killing in CF and tie the clinic defect to the molecular effect in the Cl channel. In Project 1, Drs. Welsh and Ostedgaard will focus on regulation of CFTR Cl channels by phosphorylation of the R domain. Phosphorylation is the physiologic mechanism that controls channel activity. Their studies should provide detailed functional and three-dimensional structural information about the R domain and new insights into the regulation of CFTR. In Project 4, Drs. Zabner and Smith will focus on regulation of airway surface fluid salt concentration by CFTR Cl channels. Complementary approaches will be used to measure human airway surface fluid salt concentration both in vitro and in vivo. Novel approaches to correct the abnormal composition of airway surface fluid will also be investigated. In Project 2, Drs. McCray and Tack will investigate the biology of human beta-defensins 1 and 2 (hBD-1 and -2). These salt-inhibited defensins are anti-microbial peptides expressed in airway epithelial. Their studies will determine the cell- specific localization, this diverse beta-defensin gene family. In Project 3, Dr. Engelhardt focuses on the integrated physiology of the airways. He will specifically examine the contribution of the sub-mucosal glands to airway defense mechanisms. This project uses a novel approach to the study of mouse and tracheal xenografts in the presence and absence of sub- mucosal glands. All of the projects depend on the Cell Culture Core for tissue acquisition and development of models relevant to CF airways. Insights gained from the comprehensive approach in this SCOR will improve our understanding of the pathogenesis of CF airway disease and may lead to novel therapies.