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: 8607062
• 负责人: Lisa A Palmer
• 金额: $ 37.55万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8607062
• 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.

目前的建议确定了一种新的经肺调节的S-亚硝基化/脱亚硝基化耦合环在肺血管内皮细胞。这个反馈回路由eNOS和GSNO-R组成，eNOS由雌激素上调，GSNO-R由雄激素下调。这两种蛋白质在物理上相互作用，但这种相互作用对肺生理学和病理学的影响尚不清楚。因此，确定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， 局部S-亚硝基硫醇（SNO）的丰度对于鉴定其在正常肺血管生理学和病理学中的作用至关重要。SNO与各种肺部疾病的发展有关，其中许多疾病在表现上表现出不同的性别偏好，或在青春期通过未知机制发生严重程度的变化。在这方面，雌激素增加SNO的形成，引起GSNO-R活性的代偿性增加。因此，肺血管内皮细胞SNO暴露增加， 而GSNO-R活性没有增加（这在暴露于外源性SNO的雄性小鼠中是异常的），则产生包括肺血管重塑和PH的SNO毒性。因此，GSNO-R的异常可能减少肺血管内皮对增加的eNOS活性的保护，我们假设内皮细胞中SNO的生物利用度是由血管调节的S-亚硝基化/脱硝偶联环。这个调节环可能是 参与血管内皮细胞内eNOS活性和SNO生物利用度的调节。此外，这种调节回路的中断在PH中观察到的性别差异中起作用。 目的1：肺内皮细胞内存在GSNO-R和eNOS的相互作用。 目的2：eNOS/GSNO-R相互作用的亚细胞定位有助于局部SNO的生物利用度。 目的3：S-亚硝基化/脱亚硝基化调节环的破坏导致PH中观察到的性别不一致。 总之，确定该耦合环的激素调节的重要性及其与肺血管疾病性别易感性的关系将增强我们对男性/女性介导的疾病易感性/保护机制的认识，并将增加发展性别易感性的可能性。 特定的治疗剂。