Characterization of Altered Mechanosensing in Mouse Models of ECM-induced TAA

项目总结 胸主动脉瘤(Taa)是一组由复杂的疾病引起的危及生命的疾病。 不同细胞类型、不同细胞外基质(ECM)隔间的病理生理相互作用 和多种生化信号一起，使血管壁易于剥离和破裂。我们 假设，无论根本原因如何，功能失调的机械生物学是一种共同的机制 TAA的发展，因此，分子感测、转换或对抗机械应力 可能代表着药物治疗的潜在新靶点。这个PPG的重点是确定与 在结构正常的情况下，由实验升高的血压触发的细胞反应 或通过生理血流动力学负荷在遗传缺陷的基质上。项目1使用鼠标 用进行性重度马凡综合征(MFS)模型研究动脉粥样硬化的发病机制 疾病。之所以选择这种TAA的遗传模型，是因为突变的蛋白质(纤维蛋白-1)调节着几个关键的 动脉功能和动态平衡方面，包括组织完整性，内皮细胞机械转导， 血管紧张素II I型受体活性与转化生长因子β信号转导我们的提案分为两部分 结合遗传、生物力学和计算方法来阐明主要的 血管紧张素转换酶依赖和非血管紧张素受体信号通路的触发子、下游介体和靶点 MFS小鼠不同的主动脉间隔(目标1)，并评估ECM完整性的增量损失 影响主动脉细胞对诱发性高血压的生物学反应(目标2)。预期的调查结果将 通报、扩展或补充其他PPG项目进行的研究，这些项目将共同提供一个新的 组织水平上对TAA发生和发展的分子因素和细胞事件的了解 一种有效的致死性MFS小鼠模型的研究进展。

Project summary Thoracic aortic aneurysms (TAAs) are a group of life-threatening conditions driven by complex pathophysiological interactions among different cell types, distinct extracellular matrix (ECM) compartments and multiple biochemical signals that, together, predispose the vessel wall to dissection and rupture. We hypothesize that, irrespective of the underlying cause, dysfunctional mechanobiology is a shared mechanism of TAA development and consequently, that molecules sensing, transducing or countering mechanical stress may represent potential new targets for drug therapy. This PPG focuses on identifying key disease-related cellular responses that are triggered either by experimentally increased blood pressure on a structurally normal tissue or by physiological hemodynamic load on a genetically deficient matrix. Project 1 employs a mouse model of progressively severe Marfan syndrome (MFS) to characterize the latter mechanism of arterial disease. This genetic model of TAA was chosen because the mutated protein (fibrillin-1) regulates several key aspects of arterial function and homeostasis, including tissue integrity, endothelial cell mechanotransduction, angiotensin II (AngII) type I receptor (AT1r) activity and TGFβ signaling. Our proposal is organized into two specific aims that combine genetic, biomechanical and computational approaches to elucidate the primary triggers and downstream mediators and targets of AngII-dependent and AngII-independent AT1r signaling in distinct aortic compartments of MFS mice (Aim 1), and to evaluate how incremental loss of ECM integrity influences the biological responses of aortic cells to induced hypertension (Aim 2). Expected findings will inform, extend or complement the studies pursued by other PPG projects, which collectively will provide a new tissue-level understanding of the molecular factors and cellular events responsible for TAA onset and progression in a validated mouse model of lethal MFS.