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，目前尚无良好的治疗方法。 我们已经提出，特定的遗传缺陷和环境的侮辱，改变不同方面的， 细胞和ECM之间的生理相互作用导致TAA。因此，我们认为TAA是一种 改变了血管机械生物学在这个项目资助申请中，我们将重点关注生物学 主动脉细胞，即平滑肌细胞（SMC）和内皮细胞（EC）对两种主要的细胞因子的反应。 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。我们将 检查正常或受损小鼠动脉瘤发展过程中EC和SMC的反应 ECM，同时关注通过血管紧张素II和转化生长因子β的信号传导， 血流动力学负荷增加。我们将研究多种小鼠模型对血流变化的反应， 压力，以及其他遗传干扰，重点是AT 1 r，TGF β 1/2，TGFβ和流量依赖性 发信号和激活（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生物力学评估和生物信息学进行分析， 模型核心。例如，来自所有小鼠模型的小鼠亚组将在计算和生物学实验中进行测试。 生物力学参数和所有差异表达的实验生物力学评估核心 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。以这种方式 所有四个项目的信息可以大量应用，产生更大的意义。我们的目的是 从生物力学和细胞信号的变化中开发新的解释， 关于ECM调制的假设，除了重要的信号节点和新的启示， 潜在的药物治疗。我们建议采用一种一致的、综合的方法， 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的 以协同的方式洞察。

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.