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

项目摘要 胸主动脉瘤（TAA）是一组由复杂的 不同细胞类型、不同细胞外基质（ECM）区室之间的病理生理相互作用 以及多种生化信号，这些信号一起使血管壁易于剥离和破裂。我们 假设，不管潜在的原因，功能失调的机械生物学是一个共同的机制 因此，分子传感，转导或对抗机械应力 可能是药物治疗的潜在新靶点。本PPG侧重于确定关键疾病相关 这些细胞反应要么是由实验性升高的血压触发的， 组织或通过遗传缺陷基质上的生理血液动力学负荷。项目1使用鼠标 进行性严重马凡综合征（MFS）模型，以表征动脉硬化的后一种机制。 疾病之所以选择这种TAA的遗传模型，是因为突变的蛋白质（tagin-1）调节了几个关键的 动脉功能和体内平衡方面，包括组织完整性，内皮细胞机械转导， 血管紧张素II（AngII）I型受体（AT 1 r）活性和TGFβ信号传导。我们的建议分为两部分 结合联合收割机遗传学、生物力学和计算方法来阐明 血管紧张素II依赖性和血管紧张素II非依赖性AT 1 r信号传导的触发因子、下游介质和靶点， MFS小鼠的不同主动脉隔室（目的1），并评估ECM完整性的增量损失如何 影响主动脉细胞对诱导性高血压的生物学反应（目的2）。预期结果将 通知，扩展或补充其他PPG项目所进行的研究，这些项目将共同提供一个新的 在组织水平上了解TAA发病的分子因素和细胞事件， 在经验证的致死性MFS小鼠模型中的进展。

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.