Mitochondrial network remodeling and the development of the hyper-proliferative and antiapoptotic endothelial phenotype.

线粒体网络重塑以及过度增殖和抗凋亡内皮表型的发展。

• 批准号: 10468117
• 负责人: Ting Wang
• 金额: $ 40.41万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468117
• 关键词: Adaptor Signaling Protein; Apoptosis; Apoptosis Inhibitor; Apoptotic; Attenuated; Automobile Driving; Autophagocytosis; Blood Pressure; Blood Vessels; Blood flow; Cardiopulmonary; Cell Proliferation; Child; Childhood Injury; Chimeric Proteins; Chloroquine; Complex; Congenital Heart Defects; Consumption; Data; Development; Dynamin; Endothelial Cells; Endothelium; Family member; Infant; Injury; Ligation; Link; Lung; Mechanical Stress; Mediating; Mediator of activation protein; Metabolic; Mitochondria; Modeling; Morbidity - disease rate; OPA1 gene; Pathogenesis; Pathway interactions; Phenotype; Play; Process; Proteins; Publishing; Regulatory Pathway; Role; Shunt Device; Signal Transduction; Sphingosine-1-Phosphate Receptor; Testing; Treatment Efficacy; Vascular remodeling; arteriole; base; congenital heart disorder; effective therapy; endothelial dysfunction; fasudil; hemodynamics; in vivo; lamb model; mechanical force; mitochondrial autophagy; mitochondrial dysfunction; new therapeutic target; nitration; novel therapeutic intervention; pre-clinical; pressure; protective effect; pulmonary vascular disorder; pulmonary vascular remodeling; receptor; receptor expression; response; rho GTP-Binding Proteins; sheep model; sphingosine 1-phosphate; survivin; therapeutic target; vascular injury

Project Summary Pulmonary vascular disease is responsible for significant morbidity in infants and children with common congenital heart defects that result in increased pulmonary blood flow (PBF) and pressure. There is a lack of effective therapies to limit the shared pathophysiologic features of endothelial dysfunction and vascular remodeling. Our recent studies have demonstrated that metabolic reprogramming and mitochondrial dysfunction, mediated by mechanical stress, is a core regulatory pathway underlying the vascular injury in these children. Further, we have recently identified the presence of a hyper-proliferative, anti-apoptotic endothelial phenotype in our Shunt lamb model of increased PBF and pressure that is involved in an angiogenic response and results in an increase in pulmonary arteriole number. Our data indicate that this endothelial phenotype is associated with increased expression of survivin (an anti-apoptotic protein), mitochondrial fission and increased autophagy/mitophagy. These processes are linked to a loss of NO signaling. The decreased NO signaling in our Shunt lamb model occurs, at least in part, through a decrease in ATP-mediated hsp90 activation. The massive metabolic requirement associated with hyper-proliferation requires a significant consumption of ATP. Based on these data our overall hypothesis is that the ATP consumption required to maintain the hyper- proliferative, anti- apoptotic, endothelial phenotype associated with increased PBF and pressure plays a significant role in the loss of NO signaling by attenuating hsp90 activity. Our data implicate RhoA/ROCK signaling as a master-regulator of these pathways. Studies in our lab have shown that ligation of S1PR3 receptor, induces Rho GTPase signaling and cytoskeletal remodeling. Interestingly, S1PR1 receptor, which exerts a protective effect against mechanical stress, is significantly downregulated in the lungs of our Shunt lamb model, while S1PR3 receptor expression is increased. We hypothesize that a mechanical stress mediated activation of an S1PR3 receptor-RhoA/ROCK axis is responsible for the mitochondrial fission, autophagy/mitophagy, and apoptosis that synergize to produce the hyper-proliferative, anti-apoptotic endothelial phenotype and the loss of NO signaling. Three Specific Aims (SAs) are proposed to test this hypothesis. In Aim 1, we will define the role of mitochondrial fission in the development of a hyper-proliferative endothelial phenotype and determine how this modulates NO signaling. In Aim 2, we will characterize the role played by autophagy/mitophagy in the loss of NO signaling under conditions of increased PBF and pressure and investigate the role played by the anti- apoptotic factor, survivin (Birc5). In Aim 3, we will determine whether targeting mitochondrial fission and autophagy are potential therapeutic targets in our pre-clinical Shunt lamb model. With the completion of this study, we will significantly increase our understanding of the role played by mitochondrial network remodeling and autophagy/mitophagy in the pathogenesis of pulmonary vascular disease associated with increased PBF and pressure while highlighting the application of novel therapeutic interventions.

项目概要 肺血管疾病是婴儿和儿童常见疾病的显着发病率 先天性心脏病导致肺血流量（PBF）和压力增加。缺乏 限制内皮功能障碍和血管的共同病理生理特征的有效疗法 重塑。我们最近的研究表明，代谢重编程和线粒体功能障碍， 由机械应力介导，是这些儿童血管损伤的核心调节途径。 此外，我们最近发现存在过度增殖、抗凋亡的内皮表型 在我们的分流羔羊模型中，PBF 和压力增加，参与血管生成反应并导致 肺小动脉数量增加。我们的数据表明这种内皮表型与 生存素（一种抗凋亡蛋白）表达增加、线粒体裂变和增加 自噬/线粒体自噬。这些过程与 NO 信号传导的丧失有关。我们体内的 NO 信号减少 分流羔羊模型至少部分是通过 ATP 介导的 hsp90 激活的减少而发生的。巨大的 与过度增殖相关的代谢需求需要大量消耗 ATP。基于 这些数据我们的总体假设是，维持过度增殖、抗-增殖所需的 ATP 消耗 与 PBF 和压力增加相关的凋亡、内皮表型在损失中起着重要作用 通过减弱 hsp90 活性来抑制 NO 信号传导。我们的数据表明 RhoA/ROCK 信号传导是 这些途径。我们实验室的研究表明，S1PR3 受体的连接可诱导 Rho GTPase 信号传导 和细胞骨架重塑。有趣的是，S1PR1受体对机械损伤发挥保护作用 在我们的 Shunt 羔羊模型的肺部，压力显着下调，而 S1PR3 受体表达 增加。我们假设机械应力介导 S1PR3 受体 RhoA/ROCK 的激活 轴负责线粒体裂变、自噬/线粒体自噬和细胞凋亡，它们协同作用产生 过度增殖、抗凋亡的内皮表型和 NO 信号传导的丧失。三个具体目标 建议（SA）来检验这一假设。在目标 1 中，我们将定义线粒体裂变在 过度增殖内皮表型的发展并确定其如何调节 NO 信号传导。在 目标 2，我们将描述自噬/线粒体自噬在一定条件下 NO 信号丢失中所起的作用 增加的 PBF 和压力并研究抗凋亡因子生存素 (Birc5) 所发挥的作用。在 目标 3，我们将确定靶向线粒体裂变和自噬是否是潜在的治疗靶点 在我们的临床前分流羔羊模型中。随着这项研究的完成，我们将大大提高我们的 了解线粒体网络重塑和自噬/线粒体自噬在 肺血管疾病的发病机制与PBF和压力增加相关，同时强调 新的治疗干预措施的应用。