Transforming Growth Factor-beta Signaling Pathways in Thoracic Aortic Aneurysms

描述(由申请人提供)： 胸主动脉瘤(TAA)是一种潜在的破坏性疾病过程，通常在没有症状的情况下通过破裂而导致死亡。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)的结构和组成发生变化。目前还没有有效的非手术临床治疗方案，可以阻止或逆转动脉瘤形成过程中的主动脉重构过程。虽然目前的数据表明，这种病理性重构是基质金属蛋白酶及其内源性组织抑制物表达/丰度发生显著时空变化的结果，但对调控重构过程的上游信号事件关注较少。一种已知可以改变ECM的结构和组成并在血管重塑中发挥重要作用的上游信号蛋白是转化生长因子-β(TGF-β)。对TAA发展过程中的转化生长因子-b信号通路的检测显示，信号通路从转化生长因子-BRI介导的途径转变为ALK-1介导的途径。因此，目前的建议将检验通过ALK-1途径的信号驱动异常血管重塑和TAA发展的中心假设。利用TAA小动物模型、分离的主动脉成纤维细胞的细胞研究以及特定基因/抑制剂的体内释放，将通过以下方面验证这一假说：(1)建立TAA发育过程中转化生长因子-b信号的变化与细胞外基质降解/沉积决定因素的变化之间的关系；(2)证明基质金属蛋白酶/组织基质金属蛋白酶的表达和丰度的变化是通过转化生长因子-b对主动脉成纤维细胞的影响来调节的；以及(3)证明可以通过在体内修改转化生长因子-b信号来改变基质金属蛋白酶/组织基质金属蛋白酶的丰度和主动脉的扩张。这组独特的研究将确定改变的转化生长因子-b信号与细胞外基质重塑的降解性决定因素的产生之间的关系。这项提案的结果将为TAA的发展提供特殊的洞察力，并可能确定可用于扰乱TAA形成和进展的重要目标。 公共卫生相关性： 胸主动脉瘤(TAA)是一种潜在的破坏性疾病，通常缺乏特定的症状，直到主动脉破裂时才被注意到，从而导致显著的发病率和死亡率。目前，TAA患者尚无非侵入性介入治疗方法。直到主动脉破裂的风险超过手术修复的风险，才会启动“观察和等待”监测计划。由于退伍军人人口的迅速老龄化和心血管疾病的高发病率，人们越来越关注动脉瘤发病率的增加，进一步的诊断和治疗进步至关重要。本提案将评估转化生长因子-b信号通路的关键组成部分，以努力了解转化生长因子-b信号在TAA疾病病因学中的作用。阐明潜在的机制可能有助于制定策略以阻止TAA的形成，甚至逆转TAA的进展，并将对退伍军人和广大公众具有重要的诊断、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.