Altered Mechanotransduction as a Therapeutic Target for Thoracic Aortic Aneurysm

总体--项目摘要 胸主动脉瘤(TAA)是一组危及生命的疾病，目前还没有很好的治疗方法。 我们已经提出，特定的遗传缺陷和环境侮辱改变了 细胞与细胞外基质之间的生理相互作用导致TAAs。因此，我们认为TAA是一种 改变了血管机械生物学。在本计划的项目资助申请中，我们将重点关注生物 血管平滑肌细胞(SMC)和内皮细胞(EC)对两种主要成分的反应 疾病的物理决定因素，即ECM完整性降低和血流动力学负荷增加。我们会 检测正常或受损小鼠动脉瘤形成过程中内皮细胞和平滑肌细胞的反应 ECM，同时专注于通过血管紧张素II和转化生长因子β反应信号 血流动力学负荷增加。我们将检查多个鼠标模型对流量变化的反应， 压力和其他遗传扰动，集中在AT1r、TGFBR1/2、转化生长因子β和依赖于流的 信令和激活(例如，VECAD和PECAM)。细胞和组织变化的后果将是 分析了我们的计算和实验生物力学评估和生物信息学 模特核心。例如，来自所有小鼠模型的小鼠的子集将在计算和 实验生物力学评价指标与各参数的差异性表达 来自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。通过这种方式， 来自所有四个项目的信息都可以批量应用，产生的意义要大得多。我们的意图是 从生物力学和细胞信号的变化中开发新的解释以产生新的可测试性 关于ECM调制的假设--兼论重要信令节点的揭示和新颖 潜在的药物疗法。我们建议采用一致、综合的方法，使用独特但互补的方法 在几种条件下研究动脉瘤发生和发展的小鼠模型将产生独特的 以协同的方式获得洞察力。

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.