Regulation of ENaC by Serine Proteases in Airways

这一研究生涯奖旨在发展首席研究员(PI)的科学技能，在研究呼吸道中丝氨酸蛋白酶对上皮钠通道(ENaC)的调节的背景下。在获奖之前，PI研究了介导粘液纤毛清除的呼吸道上皮过程，多年来一直处于囊性纤维化(CF)和上皮细胞生物学的前沿。最近，PI及其合作者开始描述位于细胞表面的内源性丝氨酸蛋白酶活性对ENaC功能的影响。通过这一奖项，PI将确定这一调节系统的特定组件(蛋白水解酶和抗蛋白酶)，并将阐明丝氨酸蛋白酶调节ENAC的机制。重要的是，根据先前观察到的呼吸道表面液体的特定性质影响ENaC功能，PI将测试这种外源蛋白是否介导ENaC对呼吸道表面液体的紧张度和体积的反应。由于ENaC功能、呼吸道表面液体容量和粘液纤毛清除之间的密切联系，这些研究有望提供关于人类呼吸道如何以一种有助于维持肺防御的方式对局部环境做出反应的重要信息。此外，由于ENaC多动是慢性肺病的基础，在这一领域获得的见解可能会转化为这种致命遗传病的新治疗方法。随后的职业发展计划包括专业研究技术方面的培训，如免疫组织化学、原位杂交、广泛的生化技术和单离子通道动力学分析。此外，还将包括有重点的课程作业和参加一系列科学会议和研讨会。PI的长期目标是对呼吸道防御的基本要素--CF肺部疾病提供重要的新见解，并将这些发现应用于CF肺部疾病的新疗法的开发。

This research career award is designed to develop the scientific skills of the primary investigator (PI), within the context of studying the regulation of the epithelial sodium channel (ENaC) by serine proteases in airways. Prior to the award, the PI has studied airway epithelial processes that mediate mucociliary clearance, have been at the forefront of cystic fibrosis (CF) and epithelial cell biology for a number of years. Recently, the PI and collaborators have begun to describe the impact that endogenous serine proteases activity located on cell surfaces has on ENaC function. With this award, the PI will identify specific components of this regulatory system (protease, anti-protease) and will elucidate the mechanism by which serine proteases regulate ENAC. Importantly, based on prior observations that specific properties of airway surface liquid effect ENaC function, the PI will test whether this exo-protease mediates ENaC responses to airway surface liquid tonicity and volume. Because of the tight link between ENaC function, airway surface liquid volume, and mucociliary clearance, these studies are expected to provide important information regarding how human airways respond to their local environment in a way that facilitates the maintenance of lung defense. Also, because ENaC hyperactivity underlies CF lung disease, insights gained in this area may be translated into new therapeutic approaches for this lethal genetic disease. The career development plan that will be followed includes training in specialized research techniques, such as immunohistochemistry, in situ hybridization, a broad range of biochemical techniques, and single ion channel kinetic analysis. Also, focused coursework and participation in an array of scientific meetings and seminars will be included. The PI's long term goals are to provide important new insights into the basic elements of airway defense, CF lung disease, and to bring these findings to the development of novel therapies for CF lung disease.