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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.

项目总结/文摘