S-nitrosothiol signaling in pulmonary epithelial cells

肺上皮细胞中的 S-亚硝基硫醇信号传导

• 批准号: 8141724
• 负责人: Lisa A Palmer
• 金额: $ 41.04万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8141724
• 关键词: Address; Affect; Air; Androgens; Asthma; Biological Availability; Biology; Blood Vessels; Cilia; Coupling; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Development; Disease; Dissociation; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Epithelium; Esters; Estrogens; Feedback; Female; Gender; Heat-Shock Proteins 90; Hormones; Human; Humulus; In Vitro; Knowledge; Lead; Liquid substance; Location; Lung; Lung diseases; Mediating; Mus; Nitric Oxide Synthase; Oxidoreductase; Pathology; Physiology; Play; Predisposition; Protein S; Proteins; Puberty; Pulmonary Hypertension; Regulation; Risk; Role; S-Nitrosoglutathione; S-Nitrosothiols; Severities; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic Agents; Toxic effect; Ubiquitination; Up-Regulation; Vascular Diseases; Vascular Endothelium; Vascular remodeling; airway epithelium; base; cystic fibrosis airway epithelia; gender preference; genetic regulatory protein; hormone regulation; human NOS3 protein; in vivo; male; new therapeutic target; novel; respiratory

The current proposal identifies a novel hormonally regulated S-nitrosylation/denitrosylation coupling loop in the pulmonary vascular endothelium. This feedback loop consists of eNOS, which is up-regulated by estrogens, and GSNO-R, which is down-regulated by androgens. These two proteins physically interact, however the impact of this interaction on pulmonary physiology and pathology is unknown. Thus, defining the subcellular location of this interaction within the endothelial cell and the influence of this relationship on local S-nitrosothiol (SNO) abundance is of paramount importance to identifying its role in normal pulmonary vascular physiology and pathology. SNOs have been implicated in the development of various pulmonary diseases, many of which display distinct gender preferences in presentation or a change in severity at puberty by unknown mechanisms. In this respect, estrogen increases SNO formation causing a compensatory increase in GSNO-R activity. Thus, increased pulmonary vascular endothelial SNO exposure without increases in GSNO-R activity, which is abnormal in male mice exposed to exogenous SNOs, produces SNO toxicity including pulmonary vascular remodeling and PH. Thus, abnormalities in GSNO-R may diminish protection of pulmonary vascular endothelium to increased eNOS activity, resulting in increased risk to develop PH. We hypothesize that SNO bioavailability in the endothelium is regulated by a hormonally regulated S-nitrosylation/denitrosylation coupling loop. This regulatory loop may be involved in the regulation of eNOS activity and SNO bioavailability within the vascular endothelium Moreover, disruption of this regulatory loop plays a role in the gender divergence seen in PH. Three hypotheses will be examined. Aim 1: GSNO-R and eNOS crosstalk exists within the pulmonary endothelium. Aim 2: Subcellular location of eNOS/GSNO-R interaction contributes to local SNO bioavailability. Aim 3: Disruption of this S-nitrosylation/denitrosylation regulatory loop contributes to the gender discordance seen in PH. In summary, defining the importance of the hormonal regulation of this coupling loop and its relationship to gender susceptibility of pulmonary vascular disease will enhance our knowledge on the mechanisms of male/female mediated susceptibility/protection to disease and will increase the potential to develop gender specific therapeutic agents.

目前的建议确定了肺血管内皮中一个新的激素调节的s -亚硝基化/脱硝基化偶联环。这个反馈回路由eNOS和GSNO-R组成，前者被雌激素上调，后者被雄激素下调。这两种蛋白在物理上相互作用，然而这种相互作用对肺生理和病理的影响尚不清楚。因此，定义这种相互作用在内皮细胞内的亚细胞位置以及这种关系对内皮细胞的影响