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.
S-nitrosylation signaling is relevant to virtually every aspect of respiratory/ventilatory biology. In Project 1, we will focus on defining the biology of ainway S-nitrosylation downstream of NOS activation, particularly as it relates to developing therapies for cystic fibrosis. In Project 2, we will study S-nitrosylation signaling in pulmonary endothelial biology as it relates to gender effects in pulmonary arterial hypertension. In Project 3, we will study S-nitrosylation signaling in neurorespiratory biology as it relates to apnea. We anticipate that the results of these focused and integrated studies will be of direct relevance to the treatment of airways diseases, pulmonary vascular diseases, and apnea. Additionally, we anticipate novel insights of therapeutic relevance to emerge from the collaborative work of the investigators in this Program Project.
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