Altered Mechanotransduction as a Therapeutic Target for Thoracic Aortic Aneurysm

改变机械传导作为胸主动脉瘤的治疗靶点

基本信息

批准号：
9883023
负责人：
DANIEL B RIFKIN
金额：
$ 240.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
2018-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883023
关键词：
Affect Aneurysm Angiotensin II Angiotensin II Receptor Angiotensinogen Antihypertensive Agents Aorta Applications Grants Area Binding Proteins Biochemical Bioinformatics Biological Biomechanics Blood Pressure Blood Vessels Blood flow Cells Characteristics Chest Clinical Complement Complex Cytokine Receptors Data Development Disease Elastic Fiber Endothelial Cells Extracellular Matrix FBN1 Failure Genes Genetic Goals Homeostasis Human ITGA5 gene In Situ In Vitro Individual Inflammatory Infusion procedures Institution Lead Life Ligands Marfan Syndrome Measures Mechanical Stress Mechanics Mediator of activation protein Medical Modeling Molecular Mus Mutation Operative Surgical Procedures Pathogenesis Pathology Pathway interactions Pattern Pharmacology Pharmacotherapy Physiological Program Research Project Grants Property Protein Isoforms Receptor Cell Receptor Signaling Regulation Relaxation Role Signal Transduction Signaling Molecule Smooth Muscle Myocytes Specific qualifier value Specimen Stimulus Stretching TGFBR1 gene Techniques Testing Thoracic Aortic Aneurysm Thoracic aorta Tissues Transforming Growth Factor beta Vasoconstrictor Agents cadherin 5 cell type data integration differential expression experimental study hemodynamics improved outcome in vivo insight interdisciplinary approach mechanical force mechanical load mechanotransduction mouse model mutant novel novel therapeutics postnatal pressure prevent prophylactic protective effect protein activation receptor response shear stress therapeutic target transcriptome sequencing

项目摘要

Overall - Project Summary Thoracic aortic aneurysms (TAA) are a group of life threatening conditions for which there is no good therapy. We have proposed that specific genetic defects and environmental insults that alter distinct aspects of the physiological interactions amongst cells and ECM lead to TAAs. As such, we view TAA as a disease of altered vascular mechanobiology. In this Program Project Grant application, we will focus on the biological responses of aortic cells, namely smooth muscle cells (SMC) and endothelial cells (EC) to the two major physical determinants of disease, namely decreased ECM integrity and increased hemodynamic loads. We will examine responses of ECs and SMCs during aneurysm development in mice with normal or compromised ECM while focusing on signaling through angiotensin II and transforming growth factor beta in response to increased hemodynamic loads. We will examine responses of the multiple mouse models to changes in flow, pressure, and additional genetic perturbations focusing on AT1r, TGFBR1/2, TGFβ, and flow-dependent signaling and activation (e.g., VECAD and PECAM). Consequences of cellular and tissue changes will be analyzed with our Computational and Experimental Biomechanical Assessment and Bioinformatics and Modeling Cores. For example, a subset of mice from all mouse models will be tested in the Computational and Experimental Biomechanical Assessment core for biomechanical parameters and all differentially expressed gene data from RNAseq experiments will be analyzed in the Bioinformatics and Modeling core. In this way the information from all four projects can be applied en mass yielding considerably more significance. Our intent is to develop novel interpretations from the changes in biomechanics and cell signaling to yield new testable hypothesis concerning ECM modulation in addition to the revelation of important signaling nodes and novel potential drug therapies. We propose that a consistent, integrated approach, using unique but complementary mouse models for aneurysm genesis and progression, studied under several conditions will yield unique insights in a synergistic manner.

总体 - 项目摘要胸动脉瘤（TAA）是一群威胁生命的疾病，没有良好的疗法。我们提出，特定的遗传缺陷和环境伤害改变了不同方面细胞和ECM之间的生理相互作用导致TAA。因此，我们将TAA视为血管机制改变。在此计划项目赠款应用程序中，我们将重点放在生物学上主动脉细胞，即平滑肌细胞（SMC）和内皮细胞（EC）的反应疾病的身体决定剂，即降低了ECM完整性和增加的血液动力学负荷。我们将检查正常或受损的小鼠动脉瘤发育过程中EC和SMC的反应 ECM专注于通过血管紧张素II信号传导并转化生长因子β的响应血液动力学负荷增加。我们将检查多个鼠标模型以改变流量的响应，压力和其他遗传扰动重点是AT1R，TGFBR1/2，TGFβ和流动依赖性信号传导和激活（例如，VECAD和PECAM）。细胞和组织变化的后果将是通过我们的计算和实验性生物力学评估以及生物信息学以及建模核心。例如，所有鼠标模型的小鼠子集将在计算和生物力学参数的实验生物力学评估核心和所有表达的所有表达 RNASEQ实验的基因数据将在生物信息学和建模核心中进行分析。这样所有四个项目的信息都可以应用于大规模，从而仔细地产生更重要的意义。我们的意图是从生物力学和细胞信号的变化中开发出新的解释，以产生新的可测试除了重要的信号节点和新颖的启示外，关于ECM调制的假设潜在的药物疗法。我们建议使用独特但完整的一致，集成的方法在几种条件下研究的动脉瘤发生和进展的小鼠模型将产生独特以协同的方式见解。