Regulation of ENaC by Serine Proteases in Airways

该研究职业奖旨在培养主要研究者（PI）在研究气道中丝氨酸蛋白酶对上皮钠通道（ENaC）的调节方面的科学技能。在获奖之前，PI已经研究了介导粘膜纤毛清除的气道上皮过程，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和合作者已经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。有了这个奖项，PI将确定这个调节系统的特定组成部分（蛋白酶，抗蛋白酶），并将阐明丝氨酸蛋白酶调节ENAC的机制。重要的是，基于先前观察到的气道表面液体的特定特性对ENaC功能的影响，PI将测试这种外显蛋白酶是否介导ENaC对气道表面液体张力和体积的反应。由于ENaC功能、气道表面液体体积和粘膜纤毛清除之间的紧密联系，这些研究有望提供关于人类气道如何以促进维持肺防御的方式对局部环境作出反应的重要信息。此外，由于ENaC过度活跃是CF肺病的基础，因此在这一领域获得的见解可能会转化为这种致命遗传疾病的新治疗方法。接下来的职业发展计划包括专业研究技术的培训，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，重点课程和参加一系列科学会议和研讨会也将包括在内。PI的长期目标是为气道防御，CF肺病的基本要素提供重要的新见解，并将这些发现用于CF肺病的新疗法的开发。

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.