Characterization of TGFB-Dependent Mechanoresponses by Aortic Smooth Muscle Cells

项目摘要 胸主动脉瘤（TAAs）影响年轻和老年男性和女性，并导致显著的 发病率和死亡率。近年来的研究结果表明，一个异常的活动或信号通过 转化生长因子-β（TGFβ）在TAAs中起重要作用，但关于其在TAAs中的作用仍存在争议。 精确的机制。这种缺乏了解继续阻碍着确定改进的治疗方法。 最近一项备受期待的氯沙坦（一种血管紧张素II）临床试验失败， 受体拮抗剂我们和其他人最近假设， 表明TAAs是由受损的细胞机械感受和机械调节引起的。 细胞外基质赋予主动脉壁结构完整性。重要的是，TGFβ可以在 部分，作为一个重要的机械传感器-其生产和激活是机械敏感的， 下游基因产物包括对传感至关重要的收缩蛋白， 调节响应其增加的信号传导而产生的细胞外基质。 我们工作的目标是测试新的假设之间的相互作用的结构和教学的作用， 改变的TGFβ信号传导，平滑肌细胞对改变的壁应力的机械感受（特别是那些由于 高血压，TAAs的主要危险因素），以及HLA-I的完整性，HLA-I是一种必需的糖蛋白， 与弹性蛋白结合形成弹性纤维。为此，我们将使用一种新的基因组合， 改良的小鼠模型、诱导性高血压的体内模型和TAA的临床标本。具体地说， 我们将描述胸主动脉中平滑肌细胞对增加的壁应力的反应， 破坏依赖于TGFβ信号传导并导致主动脉壁适应不良重塑的β-淀粉样蛋白-1。的 因此，我们的工作结果将为TGFβ信号转导在以下情况下的作用提供第一个机制研究： 高血压（TAAs的主要危险因素）和受损的细胞外基质（细胞外基质蛋白-1，TAAs的原因）， 大多数综合征TAAs），同时首次测试最近提出的假设，即功能障碍 平滑肌机械感应和基质的机械调节是TAA的许多不同原因的基础。在 特别是，我们认为，平滑肌细胞将调用一个萎缩的过程，如果他们感觉应力低于 即使在实际应力正常或高于正常的情况下， 发展缓慢。主动脉平滑肌细胞TGFβ依赖性机械反应的特征 肌肉细胞可以识别新的分子靶点来治疗TAA，这是一种致命的疾病， 药物治疗.

PROJECT SUMMARY Thoracic aortic aneurysms (TAAs) affect young and old males and females and are responsible for significant morbidity and mortality. Findings over recent years suggest that an aberrant activity of or signaling through transforming growth factor-beta (TGFβ) plays important roles in TAAs, yet controversy remains regarding the precise mechanisms. This lack of understanding continues to hinder the identification of improved therapeutic approaches as revealed by the recent failure of a highly anticipated clinical trial of losartan, an angiotensin-II receptor antagonist. We and others recently hypothesized that the collection of predisposing genetic mutations suggests that TAAs result from a compromised cellular mechanosensing and mechanoregulation of the extracellular matrix that endows the aortic wall with its structural integrity. Importantly, TGFβ can be viewed, in part, as an important mechanotransducer – its production and activation are mechanosensitive and its downstream gene products include the contractile proteins that are fundamental to sensing and regulating the extracellular matrix that is produced in response to its increased signaling. The goal of our work is to test novel hypotheses on interactions among the structural and instructional roles of altered TGFβ signaling, smooth muscle cell mechanosensing of altered wall stresses (particularly those due to hypertension, a primary risk factor for TAAs), and the integrity of fibrillin-1, an essential glycoprotein that associates with elastin to form elastic fibers. Towards this end, we will use a combination of new genetically modified mouse models, in vivo models of induced hypertension, and clinical specimens of TAAs. Specifically, we will characterize responses of smooth muscle cells in the thoracic aorta to increased wall stresses and disrupted fibrillin-1 that depend on TGFβ signaling and lead to maladaptive remodeling of the aortic wall. The results of our work will thereby provide the first mechanistic investigation of roles of TGFβ signaling in cases of hypertension (a major risk factor for TAAs) and compromised extracellular matrix (fibrillin-1, the cause of the majority of syndromic TAAs) while testing, for the first time, the recently proposed hypothesis that dysfunctional smooth muscle mechanosensing and mechanoregulation of matrix underlies many different causes of TAAs. In particular, we suggest that smooth muscle cells will invoke an atrophic process if they sense stresses lower than homeostatic even in cases wherein the actual stress is normal or higher than normal, which will drive the wall toward aneurysmal development. The characterization of TGFβ-dependent mechanoresponses by aortic smooth muscle cells may identify new molecular targets to treat TAAs, a lethal disease and without current pharmacotherapy.