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

• 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
• 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

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，距诊断大约六年。多达两万分之一的人受到影响， 并且没有可用的疗法可以治愈或预防这种疾病。 PAH的特点是肺动脉内皮细胞 细胞（PAEC）和平滑肌细胞（PASMC）功能障碍导致肺血管阻力增加 以及因右心衰竭而死亡。异常的血流动力学是某些人中 PAH 的主要原因 患者，并且在所有情况下都可能有助于进展。 PAH 中的小肺动脉暴露于 剪切应力和压力都会增加。先前已证明增加的剪切应力 导致 EC 变化类似于 PAH 中所见的变化。雷纳博士获得的初步数据表明 PAH 患者的 PAEC 对病理性高剪切应力具有不同的转录组反应 与对照相比。这表明患者剪切敏感通路的异常可能是 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相结合 驱动血管功能障碍并促进 PAH。雷纳博士的研究项目专注于应用新颖的 生物工程技术对PAH的研究。他的研究计划将使用电阻耦合微流体 允许单独和组合评估压力和剪切力的装置。雷纳博士有 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 评估 EC-SMC 信号传导和协调的血管行为。 Rayner 博士的研究目标是 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 电阻耦合微流体平台； 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、生物信息学和血管学方面必要的额外培训 工程。雷纳博士将通过正式教学、体验式培训、 以及由具有相关专业知识的世界级科学家团队的密切指导。这些新技能将增强 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。有着自己独特的 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 在他提出的 K08 研究期即将结束时提交一份有竞争力的 R01 提案。