Hemodynamic Contributions to Vascular Dysfunction in Pulmonary Arterial Hypertension

项目摘要/摘要 肺动脉高压(PAH)是一种进行性和最终致命性疾病，中位生存期。 尽管接受了现代治疗，但确诊后仍持续了大约六年。每2万人中就有1人受到影响， 而且没有可用的治疗方法来治愈或预防这种疾病。以肺动脉内皮细胞为特征的PAH 细胞(PAEC)和平滑肌细胞(PASMC)功能障碍导致肺血管阻力增加 以及右心衰竭致死。血流动力异常是部分患者发生PAH的主要原因 患者，而且在所有情况下都可能促进进展。PAH中的小肺动脉暴露于 剪应力和压力力都有所增加。此前已有研究表明，剪切应力增加会导致 原因是EC的变化与PAH中的变化相似。雷纳博士获得的初步数据显示， PAH患者的PAEC对病理性高剪应力有不同的转录反应 与对照组相比。这表明，患者在剪切敏感通路中的异常可能是一种 PAH中潜在的统一机制，可能为未来的治疗提供靶点。 雷纳博士的总体目标是定义剪切力和压力力如何与潜在的患者因素相结合 导致血管功能障碍，促进PAH。雷纳博士有一个专注于应用小说的研究项目 生物工程技术对多环芳烃的研究他的研究计划将使用一种电阻耦合的微流控 允许单独和组合评估压力和剪切力的装置。雷纳博士已经 还开发了一种新的单芯片肺小动脉(AOC)模型，该模型将在本提案中使用 评估EC-SMC信号和协调的血管行为。雷纳博士的研究目标将是 通过三个目标完成：1)评估剪切和压力对控制和PAH PAECs的影响 电阻耦合微流控平台；2)确定压力和患者因素如何影响细胞 仅PASMC的AOCs的表型；3)确定血流动力学和患者因素对细胞的影响 患者特有的多细胞AOC模型中的表型和PAEC至PASMC信号转导。 这些具体目标与雷纳博士职业发展计划的主要培训目标非常一致，该计划 是在肺血管细胞生物学、生物信息学和血管方面获得必要的额外培训 工程学。雷纳博士将通过正规教学、体验式培训、 并由具有相关专业知识的世界级科学家团队提供密切指导。这些新技能将增强 他在生物工程和翻译多环芳烃研究方面的背景，并促进了他开发 成为一名独立的内科医生兼科学家，从事多环芳烃的基础和翻译研究。带着他自己独特的 工程血管平台和通过这项研究产生的数据，雷纳博士将处于有利地位 在他建议的K08研究期接近尾声时提交一份具有竞争力的R01提案。

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a progressive and ultimately fatal disease with a median survival from diagnosis of approximately six years despite modern treatments. Up to 1 in 20,000 people are affected, and no available therapies cure or prevent this disease. PAH is characterized by pulmonary arterial endothelial cell (PAEC) and smooth muscle cell (PASMC) dysfunction leading to increased pulmonary vascular resistance and death from right heart failure. Abnormal hemodynamic forces are the primary cause of PAH in some patients, and in all cases may contribute to progression. The small pulmonary arteries in PAH are exposed to both increases in shear stress and pressure forces. Increased shear stress has previously been shown to cause EC changes mimicking those seen in PAH. Dr. Rayner has obtained preliminary data showing that PAECs from subjects with PAH have divergent transcriptomic responses to pathologically high shear stress when compared with controls. This suggests that patient abnormalities in shear-sensitive pathways may be a potential unifying mechanism in PAH that could provide targets for future therapeutics. Dr. Rayner’s overall goal is to define how shear and pressure forces combine with underlying patient factors to drive vascular dysfunction and promote PAH. Dr. Rayner has a research program focused on applying novel bioengineering techniques to the study of PAH. His research proposal will use a resistor-coupled microfluidic device to allow pressure and shear forces to be evaluated both individually and in combination. Dr. Rayner has also developed a novel pulmonary arteriole-on-a-chip (AOC) model that will be employed in this proposal to evaluate EC-SMC signaling and coordinated vascular behavior. Dr. Rayner’s research goal will be accomplished through three aims: 1) Evaluate the effects of shear and pressure on control and PAH PAECs in a resistor-coupled microfluidic platform; 2) Determine how pressure and patient factors influence cell phenotypes in PASMC-only AOCs; 3) Identify the effect of hemodynamic and patient factors on cell phenotypes and PAEC to PASMC signaling within patient-specific multicellular AOC models. These specific aims are well-aligned to the main training aims of Dr. Rayner’s Career Development Plan, which are to gain essential additional training in pulmonary vascular cell biology, bioinformatics, and vascular engineering. Dr. Rayner will gain these skills through a combination of formal didactics, experiential training, and close mentorship by a world-class team of scientists with relevant expertise. These new skills will augment his background in bioengineering and translational PAH research and facilitate his overall goal of developing into an independent physician-scientist doing basic and translational research on PAH. With his own unique engineered vascular platforms and the data generated through this research, Dr. Rayner will be well-positioned to submit a competitive R01 proposal near the end of his proposed K08 research period.