Altered Mechanotransduction

项目摘要 我们试图阐明控制转化生长因子激活的生物力学机制 TGF β是胸主动脉瘤（TAA）进展的主要介质。在此PPG应用程序中 我们提出了一个具有挑战性的建议，即细胞使用TGF β的潜伏形式，它存在于细胞中。 细胞外基质（ECM）作为生物力学变化的传感器。当周围的基质发生变化时 由于固有的结构突变或周围力量的变化，如血压，TGF β是 动员起来改造EMC为了了解控制潜伏性TGF β的机制， 动员，我们必须确定特定的个别成分的潜在的TGF β复合物。我们将专注于 TGF β在两种互补类型血管病变发展中的特性;一种涉及 患有马凡氏综合征（MFS）并死于TAA的突变小鼠。另一个模型使用正常小鼠 其髂动脉已被结扎以增加压力（缩窄模型），导致快速血管收缩 重塑，我们建议重复的压力相关的促进TAA的早期事件。因此，我们认为， 一种模型代表基质的遗传缺陷，ECM成分改变，而第二种模型 表示由于诱导应力而重塑的正常基质。我们将在目标1中鉴定 TGF β参与MFS小鼠的ECM重塑和TAA生物发生（项目1和核心B和C）。在 目的2，我们将描述参与MFS和高血压小鼠的LTBP的种类，基质重塑， 和动脉瘤形成（与项目4），并阐明LTBP是否通过TGF β或通过额外的 结构功能（项目1和4以及核心B和C）。在目标3中，我们将辨别 MFS细胞和动物更容易释放活性TGF β，当置于 机械应力（项目3和核心C），如果ECM中阻止TAA形成的变化也会影响 TGF β释放（项目1和4以及核心C）。从这些实验中获得的信息将 提供了一个潜在的TGF β如何有助于TAA的理解，从而说明了潜在的点， 药物治疗的发展。 !

Project Summary We seek to elucidate the biomechanical mechanisms that control the activation of transforming growth factor beta (TGFβ), a major mediator in the progression of thoracic aortic aneurysms (TAA). In this PPG application we have put forward the provocative proposal that cells use the latent form of TGFβ, which resides in the extracellular matrix (ECM), as a sensor of biomechanical changes. Upon alteration in the surrounding matrix due to inherent structural mutations or changes in surrounding forces, such as blood pressure, TGFβ is mobilized to remodel the EMC. We posit that to understand the mechanisms controlling latent TGFβ mobilization, we must identify the specific individual components of the latent TGFβ complex. We will focus on the properties of TGFβ in the development of two complementary types of vascular lesions; one involves mutant mice that have Marfan syndrome (MFS) and die from TAA. The other model employs normal mice whose aortas have been ligated to increase pressure (coarctation model) that results in rapid vascular remodeling, which we propose duplicates the early events in pressure-related promotion of TAA. Therefore, one model represents a genetic defect of the matrix with altered ECM composition, whereas the second model represents a normal matrix remodeled because of an induced stress. We will in Aim 1 identify the isoform of TGFβ involved in ECM remodeling and TAA biogenesis in MFS mice (with Projects 1 and Cores B and C). In Aim 2, we will characterize the species of LTBP involved in MFS and hypertensive mice, matrix remodeling, and aneurysm formation (with Project 4) and elucidate whether the LTBP acts via TGFβ or by an additional structural function (with Projects 1 and 4 and Cores B and C). In Aim 3, we will discern whether the ECM of the MFS cells and animals releases active TGFβ more readily that does normal ECM when placed under mechanical stress (with Project 3 and Core C) and if changes in the ECM that block TAA formation also affect TGFβ release (with Projects 1 and 4 and Core C). The information obtained from these experiments will provide an understanding of how latent TGFβ contributes to TAA and thereby illustrate potential points for the development of drug therapy. !