Transforming Growth Factor-beta Signaling Pathways in Thoracic Aortic Aneurysms

描述（由申请人提供）： 胸主动脉瘤（TAA）疾病是一种潜在的破坏性疾病过程，通常在没有症状的情况下因破裂而导致死亡。TAA的形成是一个多因素的过程，受到细胞和细胞外机制的影响，导致细胞外基质（ECM）的结构和组成的改变。目前还没有有效的非手术临床治疗方案，可以在动脉瘤形成期间停止或逆转主动脉重塑过程。虽然目前的数据表明，这种病理性重塑是一个显着的时空变化的基质金属蛋白酶及其内源性组织抑制剂的表达/丰度的结果，很少有人关注的上游信号事件，调节重塑过程。已知改变ECM的结构和组成并且已知在血管重塑中起重要作用的一种上游信号传导蛋白是转化生长因子-β（TGF-β）。在TAA形成过程中检查TGF-b信号传导途径，发现信号传导从TGF-bRI介导的途径转变为ALK-1介导的途径。因此，本提案将测试通过ALK-1通路的信号传导驱动异常血管重塑和TAA发展的中心假设。使用TAA的小动物模型、分离的主动脉成纤维细胞的细胞研究和特异性基因/抑制剂的体内递送，将通过以下来检验该假设：（1）建立TAA发展期间TGF-β信号传导的改变与ECM降解/沉积的决定因素的变化之间的关系;（2）证明MMP/TIMP表达和丰度的改变是由TGF-β对主动脉成纤维细胞的作用介导的;和（3）证明MMP/TIMP丰度和主动脉扩张可以通过在体内改变TGF-β信号传导来改变。这组独特的拟议研究将建立改变的TGF-β信号传导和ECM重塑的降解决定因素的产生之间的关系。该提案的结果将为TAA的发展提供特殊的见解，并可能确定重要的目标，通过这些目标可以破坏TAA的形成和发展。 公共卫生相关性： 胸主动脉瘤（TAA）疾病是一种潜在的破坏性疾病过程，通常缺乏特定的血管学，使其在主动脉破裂之前未被注意到，导致显著的发病率和死亡率。目前，没有可用于TAA患者的无创介入治疗。启动“观察和等待”监测程序，直到主动脉破裂的风险超过手术修复的风险。由于退伍军人人口迅速老龄化和心血管疾病的高患病率，人们越来越担心动脉瘤发病率增加，进一步的诊断和治疗进展至关重要。目前的建议将评估TGF-β信号通路的关键组成部分，努力了解TGF-β信号在TAA疾病的病因中的作用。阐明潜在的机制可能有助于制定阻止TAA形成甚至逆转TAA进展的策略，并将为退伍军人和广大公众带来重要的诊断，预后和治疗意义。

DESCRIPTION (provided by applicant): Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often causes death by rupture in the absence of symptoms. TAA formation proceeds by a multifactorial process, influenced by both cellular and extracellular mechanisms that result in alterations of the structure and composition of the extracellular matrix (ECM). There are currently no effective non-surgical clinical treatment protocols available which will halt or reverse the aortic remodeling process during aneurysm formation. While current data demonstrate that this pathological remodeling is a result of a significant spatiotemporal change in the expression/abundance of the matrix metalloproteinases and their endogenous tissue inhibitors, little attention has been focused on the upstream signaling events that regulate the remodeling process. One upstream signaling protein known to alter the structure and composition of the ECM, and known to play an important role in vascular remodeling is transforming growth factor-beta (TGF-b). Examination of the TGF-b signaling pathway during TAA development revealed a shift in signaling from a TGF-bRI-mediated pathway to an ALK-1- mediated pathway. Accordingly, the present proposal will test the central hypothesis that signaling through the ALK-1 pathway drives aberrant vascular remodeling and TAA development. Using a small animal model of TAA, cellular studies of isolated aortic fibroblasts, and in vivo delivery of specific genes/inhibitors, this hypothesis will be tested by: (1) establishing the relationship between alterations in TGF-b signaling and changes in the determinants of ECM degradation/deposition during TAA development; (2) demonstrating that alterations in MMP/TIMP expression and abundance are mediated by the effects of TGF-b on aortic fibroblasts; and (3) demonstrating that MMP/TIMP abundance and aortic dilatation can be altered by modifying TGF-b signaling in vivo. This unique set of proposed studies will establish the relationship between altered TGF-b signaling and the production of the degradative determinants of ECM remodeling. The outcomes of this proposal will provide exceptional insight into the development of TAA and may identify significant targets through which TAA formation and progression can be disrupted. PUBLIC HEALTH RELEVANCE: Thoracic aortic aneurysm (TAA) disease is a potentially devastating disease process which often lacks specific symptomology, rendering them unnoticed until the aorta ruptures, resulting in significant morbidity and mortality. Currently, there are no noninvasive interventional treatments available for TAA patients. A "watch and wait" surveillance program is initiated until the risk of aortic rupture outweighs the risk of the surgical repair. With a growing concern of increased aneurysm incidence due to a rapidly aging Veterans population and a high prevalence for cardiovascular disease, further diagnostic and therapeutic advancement is critical. The present proposal will assess key components of the TGF-b signaling pathway, in an effort to understand the role of TGF-b signaling in the etiology of TAA disease. Elucidating the underlying mechanisms may assist in developing strategies to arrest TAA formation or even reverse TAA progression, and will carry significant diagnostic, prognostic, and therapeutic implications for Veteran's and the public at large.