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YAP/TAZ-mediated Mechanotransduction in Pulmonary Hypertension Pathogenesis

YAP/TAZ 介导的肺动脉高压发病机制中的机械转导

基本信息

批准号：
9975912
负责人：
Paul Brian Dieffenbach
金额：
$ 16.98万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975912
关键词：
Address Advisory Committees Animal Model Arteries Atomic Force Microscopy Award Behavior Binding Biological Assay Biology Biomedical Engineering Blood Vessels Cell Proliferation Cell-Cell Adhesion Cells Cellular Morphology Cessation of life Data Dependence Development Disease Disease Progression Disease model Dyspnea Endothelial Cells Environment Equilibrium Exertion Failure Feedback Foundations Future Generations Genetic Transcription Goals Grant Growth Heart failure Histone Deacetylase Hospitals Human Hypoxemia Hypoxia In Vitro Investigation Knowledge Lung Lung diseases Manuscripts Mechanical Stress Mechanics Mediating Medicine Mentors Mentorship Modeling Molecular Monocrotaline Mus PTGS2 gene Pathogenesis Pathologic Pathway interactions Patients Phenotype Preparation Prostaglandins Proteins Public Health Schools Pulmonary Hypertension Pulmonary Vascular Resistance Pulmonary artery structure Rattus Repressor Proteins Research Right ventricular structure Rodent Rodent Model Scientist Shortness of Breath Signal Transduction Signaling Protein Slice Smooth Muscle Myocytes Stress Structure TAZ gene Tamoxifen Teaching Hospitals Techniques Therapeutic Training Training Programs Transcription Coactivator Transcriptional Coactivator with PDZ-Binding Motif Trees Up-Regulation Vascular Diseases Vascular remodeling Vasodilator Agents Ventricular Woman Work arterial remodeling arterial stiffness base career career development clinically relevant conditional knockout cyclooxygenase 2 experimental study exposed human population genetic corepressor genomic locus in vivo knock-down live cell imaging mechanical pressure mechanotransduction medical schools meetings migration monolayer mortality novel novel therapeutic intervention novel therapeutics polyacrylamide pressure prevent research and development response sensor skills small molecule transcription factor

项目摘要

PROJECT SUMMARY Pulmonary hypertension (PH) is characterized by progressive pulmonary vascular remodeling that leads to exertional dyspnea, severe hypoxemia, and ultimately to right heart failure and death. For patients with PH and significant remodeling, treatment options are limited and new therapies urgently needed. This proposal examines a novel mechanobiological feedback mechanism involving signaling by YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) that may be critical in PH development. Pulmonary artery (PA) stiffness causes right ventricular stress and is associated with increased PH mortality. Utilizing atomic force microscopy on PH lung slices, Dr. Dieffenbach has demonstrated increased PA stiffness at the cellular level in human PH and early local arterial stiffening in rodent PH models. Furthermore, increased matrix stiffness drives remodeling phenotypes in pulmonary artery smooth muscle cells and endothelial cells, indicating that PA stiffness itself can fundamentally bias cells towards pathologic behaviors. Dr. Dieffenbach has recently found that stiffness-dependent phenotypes require signaling by YAP and TAZ, transcriptional modifiers activated by mechanical stress. These data led to the hypothesis that YAP and TAZ are key sensors of the PA local mechanical microenvironment and drivers of pathologic arterial remodeling. This investigation focuses on the scope and mechanism of microenvironment-driven YAP/TAZ activation, and furthermore whether YAP/TAZ inhibition can arrest or reverse vascular remodeling in vivo. In the first aim, Dr. Dieffenbach will use cutting-edge bioengineering techniques to investigate microenvironment-driven remodeling phenotypes and their dependence on intact YAP/TAZ signaling. In the second aim, he will study specific downstream mechanisms that mediate the pro-remodeling effects of YAP/TAZ mechanoactivation. Finally, in the third aim, he will determine the impact of inhibiting YAP/TAZ activity in vivo in rodent PH models. This research will be performed at Brigham and Women’s Hospital, a core teaching hospital of Harvard Medical School, and at the Harvard School of Public Health. Dr. Dieffenbach will work under the mentorship of Dr. Fredenburgh, an expert in pulmonary vascular biology and pulmonary disease modeling, and Dr. Fredberg, an expert in bioengineering, cellular dynamics, and mechanobiology. With the guidance of his mentors and scientific advisory committee, Dr. Dieffenbach has developed a comprehensive five-year training program that includes mentored research, didactic coursework, seminars, presentations at scientific meetings, manuscript preparation, and future grant planning. Dr. Dieffenbach is dedicated to a career in academic medicine, with the long-term goal of becoming a clinician-scientist studying lung diseases driven by alterations in the mechanical microenvironment. The research and career development outlined in this award will allow Dr. Dieffenbach to develop the skills needed to launch an independent career in the mechanobiology of pulmonary disease.

项目摘要肺动脉高压（PH）的特征是进行性肺血管重构，至劳力性呼吸困难、严重低氧血症，最终导致右心衰竭和死亡。和显著的重塑，治疗选择有限，迫切需要新的治疗方法。研究了一种新的机械生物学反馈机制，涉及雅普的信号传导（是的-YAP相关蛋白）和TAZ（具有PDZ-β结合基序的转录辅激活因子），这可能在PH发展中至关重要。肺动脉（PA）僵硬导致右心室应力，并与PH升高相关 Dieffenbach博士利用原子力显微镜对PH肺切片进行研究，人PH中细胞水平的硬化和啮齿动物PH模型中的早期局部动脉硬化。此外，增加的基质硬度驱动肺动脉平滑肌细胞中的重塑表型，这表明PA硬度本身可以从根本上使细胞偏向病理行为。 Dieffenbach博士最近发现，刚度依赖性表型需要通过雅普和TAZ进行信号传导，这些数据导致了这样的假设，即雅普和TAZ可能是由机械应力激活的转录修饰因子。是PA局部机械微环境的关键传感器和病理性动脉重塑的驱动器。本研究着重于微环境驱动的雅普/TAZ激活的范围和机制，以及雅普/TAZ抑制是否可以阻止或逆转体内血管重塑。在第一个目的中，迪芬巴赫博士将使用尖端的生物工程技术来研究微环境驱动的重塑表型及其对完整雅普/TAZ信号传导的依赖性。在第二个目标中，他将研究介导雅普/TAZ机械活化的促骨重塑作用的特定下游机制。最后，在第三个目标中，他将确定在啮齿动物PH模型中抑制体内雅普/TAZ活性的影响。本研究将在哈佛核心教学医院布里格姆妇女医院进行迪芬巴赫博士将在哈佛大学医学院和哈佛大学公共卫生学院工作。肺血管生物学和肺部疾病建模专家Fredenburgh博士和Fredberg博士，他是生物工程、细胞动力学和机械生物学方面的专家。在导师的指导下，作为科学顾问委员会的一员，迪芬巴赫博士制定了一项为期五年的全面培训计划，包括指导研究，教学课程，研讨会，在科学会议上的演讲，手稿迪芬巴赫博士致力于学术医学的职业生涯，长期目标是成为一名临床科学家，研究肺部疾病，微环境。该奖项中概述的研究和职业发展将使Dieffenbach博士培养在肺部疾病的机械生物学中开展独立职业所需的技能。