Cellular S-nitrosothiol signaling in respiratory biology

描述(由申请人提供)： “呼吸生物学中的细胞S-亚硫醇信号传递”是一个项目，旨在利用弗吉尼亚大学S-亚硫醇生物学的专业知识形成一个协作中心，该中心将擅长定义S-亚硫醇在呼吸系统医学中的作用。来自我们团队和其他人的新证据表明，一氧化氮合酶激活下游基于S-亚硝硫醇(和相关的氮氧化物，如亚硝酸盐)的信号与呼吸道生物学和呼吸道疾病(如囊性纤维化、肺动脉高压和呼吸暂停)有关。然而，关于呼吸系统中S-亚硝硫醇的细胞生物学和生化仍然存在基本问题。我们的目标是建立一个领先的中心来解决这些问题，使以S-亚硝硫醇为基础的呼吸系统疾病新疗法的开发成为可能。 项目1，S-亚硝硫醇在呼吸道上皮细胞中的信号和定位，将定义一氧化氮合酶激活导致原代培养的人呼吸道上皮细胞特定细胞位置特定蛋白质的S-亚硝化的机制；我们还将确定这种S-亚硝化信号的紊乱与囊性纤维化治疗方法的发展相关的机制。 项目2，S-肺内皮细胞中的亚硝硫醇信号，将定义肺血管内皮细胞中亚硝酸化和反硝化酶之间的相互作用，以及亚硝化和反硝化之间的失衡在肺动脉高压发病机制中的作用，特别是当它与性别不一致有关时。 项目3，S-亚硫醇生物学在呼吸调节中的作用，将在颈动脉体水平上考察S-亚硫醇作为呼吸兴奋剂的作用。 该计划将广泛利用校内和校外合作，以及计划核心设施，以充分利用我们在S-亚硝硫醇生物学方面的机构优势。

DESCRIPTION (provided by applicant): "Cellular S-nitrosothiol signaling in respiratory biology" is a program designed to use the expertise in S-nitrosothiol biology at the University of Virginia to form a collaborative center that will excel in defining the roles of S-nitrosothiols in respiratory medicine. Emerging evidence from our group and others suggests that S-nitrosothiol (and related nitrogen oxides such as nitrite)-based signaling downstream from nitric oxide synthase activation is relevant to respiratory biology and airway diseases such as cystic fibrosis, pulmonary arterial hypertension, and apnea. However, fundamental questions remain regarding the cell biology and biochemistry of S-nitrosothiols in the respiratory system. Our goal is to establish a leading center to address these questions, enabling development of new, S-nitrosothiol-based therapies for respiratory diseases. Project 1, S-nitrosothiol signaling and localization in airway epithelial cells, will define mechanisms by which nitric oxide synthase activation leads to S-nitrosylation of specific proteins in specific cellular locations in primary human airway epithelial cell cultures; and we will define the mechanisms by which disorders in this S-nitrosylation signaling are relevant to the development of therapies for cystic fibrosis. Project 2, S-nitrosothiol signaling in pulmonary endothelial cells, will define the interaction between Snitrosylating and denitrosylating enzymes in the pulmonary vascular endothelium; and the role of imbalance between nitrosylation and denitrosylation in the pathogenesis of pulmonary arterial hypertension, particularly as it relates to gender discordance. Project 3, S-nitrosothiol biology in ventilatory regulation, will examine the effects of S-nitrosothiols as respiratory stimulants at the level of the carotid body. This program will make extensive use of intramural and extramural collaborations, as well as Program Core facilities, to make good use of our institutional strengths in S-nitrosothiol biology.