Hemodynamic Contributions to Vascular Dysfunction in Pulmonary Arterial Hypertension

血流动力学对肺动脉高压血管功能障碍的影响

基本信息

批准号：
10570134
负责人：
Samuel Gibson Rayner
金额：
$ 18.67万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570134
关键词：
Abnormal Cell Address Affect Basic Science Behavior Bioinformatics Biomedical Engineering Blood Vessels Blood flow Calcium Signaling Cells Cellular biology Cessation of life Collagen Communication Complex Coupled Cues Data Development Development Plans Diagnosis Disease Endothelial Cells Engineering Environmental Risk Factor Exposure to Functional disorder Future Gene Expression Profile Genetic Transcription Goals Human Immunofluorescence Immunologic Individual Investigation Laboratories Lung Mentorship Methods Microfluidic Microchips Microfluidics Modeling Modernization Morphology Pathogenesis Pathologic Pathway interactions Patients Pattern Persons Pharmacologic Substance Phenotype Physicians Physiological Play Positioning Attribute Production Proliferating Pulmonary Vascular Resistance Pulmonary artery structure Research Research Proposals Role Scientist Signal Pathway Signal Transduction Smooth Muscle Myocytes Techniques Therapeutic Therapeutic Intervention Time Training Translational Research Vascular Diseases Vascular remodeling Work arteriole career development combinatorial design hemodynamics new therapeutic target next generation sequencing novel precision medicine pressure prevent programs prototype pulmonary arterial hypertension pulmonary artery endothelial cell pulmonary vascular cells response right ventricular failure screening shear stress single-cell RNA sequencing skills success transcriptome sequencing transcriptomics

项目摘要

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.

项目概要/摘要肺动脉高压（PAH）是一种进行性且最终致命的疾病，中位生存期尽管进行了现代治疗，但自诊断起大约六年后仍有多达二万人受到影响，目前还没有可用的治疗方法来治愈或预防这种以肺动脉内皮细胞为特征的疾病。细胞（PAEC）和平滑肌细胞（PASMC）功能障碍导致肺血管阻力增加右心衰竭导致的死亡是某些人 PAH 的主要原因。患者，并且在所有情况下都可能导致肺动脉高压的小肺动脉暴露于。先前已证明剪切应力和压力的增加都会增加。 Rayner 博士获得的初步数据表明，EC 的变化与 PAH 中的变化相似。 PAH 患者的 PAEC 对病理性高剪切应力具有不同的转录组反应与对照组相比，这表明患者的剪切敏感通路异常可能是一个原因。 PAH 中潜在的统一机制可以为未来的治疗提供目标。 Rayner 博士的总体目标是定义剪切力和压力如何与潜在的患者因素结合起来 Rayner 博士有一个专注于应用新型药物的研究项目。他的研究提案将使用电阻耦合微流体的生物工程技术。 Rayner 博士拥有可以单独或组合评估压力和剪切力的装置。还开发了一种新型肺小动脉芯片（AOC）模型，该模型将在本提案中采用 Rayner 博士的研究目标是评估 EC-SMC 信号传导和协调血管行为。通过三个目标来实现：1) 评估剪切和压力对控制和 PAH PAEC 的影响 2) 确定压力和患者因素如何影响细胞仅 PASMC AOC 中的表型；3) 确定血流动力学和患者因素对细胞的影响患者特异性多细胞 AOC 模型中的表型和 PAEC 至 PASMC 信号传导。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，该计划将获得肺血管细胞生物学、生物信息学和血管方面必要的额外培训雷纳博士将通过正式教学、体验式培训的结合来获得这些技能。拥有相关专业知识的世界级科学家团队的密切指导将增强这些新技能。他在生物工程和转化性多环芳烃研究方面的背景，促进了他开发的总体目标成为一名独立的医师科学家，从事 PAH 的基础和转化研究，具有自己的独特之处。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提出的 K08 研究期即将结束时提交一份有竞争力的 R01 提案。