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-亚硝基硫醇信号传导”是一个旨在利用弗吉尼亚大学S-亚硝基硫醇生物学专业知识的项目，以形成一个合作中心，该中心将擅长定义S-亚硝基硫醇在呼吸医学中的作用。来自我们小组和其他人的新证据表明，S-亚硝基硫醇（和相关的氮氧化物，如亚硝酸盐）-基于一氧化氮合酶激活下游的信号传导与呼吸生物学和气道疾病，如囊性纤维化，肺动脉高压和呼吸暂停有关。然而，关于S-亚硝基硫醇在呼吸系统中的细胞生物学和生物化学的基本问题仍然存在。我们的目标是建立一个领先的中心来解决这些问题，从而能够开发新的基于S-亚硝基硫醇的呼吸系统疾病疗法。 项目1，S-亚硝基硫醇信号和定位在气道上皮细胞，将确定机制，一氧化氮合酶激活导致S-亚硝基化的特定蛋白质在特定的细胞位置在原代人气道上皮细胞培养物;我们将确定的机制，在这个S-亚硝基化信号的障碍是相关的囊性纤维化的治疗方法的发展。 项目2，肺内皮细胞中的S-亚硝基硫醇信号传导，将定义肺血管内皮中S亚硝基化和去亚硝基化酶之间的相互作用;以及亚硝基化和去亚硝基化之间的不平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-亚硝基硫醇生物学在呼吸调节中的作用，将研究S-亚硝基硫醇作为呼吸兴奋剂在颈动脉体水平的作用。 该计划将广泛利用校内和校外合作，以及计划核心设施，充分利用我们在S-亚硝基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.