Exploration of key proteases and validation of biomarkers in genetically triggered thoracic aortic aneurysms

项目摘要：胸主动脉瘤(TAA)的发展是异常重塑的结果。 主动脉细胞外基质(ECM)。这一过程削弱了主动脉壁，并导致粗大扩张， 通常以无症状的方式进展到破裂。有几个描述得很好的病因 有助于TAA的形成和发展。这些包括遗传综合征，以及非综合征 可遗传的先天遗传。目前的治疗选择是有限的，包括外科重建或腔内直视手术。 血管干预；这两种方法都不涉及导致疾病的潜在机制。这很好 描述了TAA同时受到细胞内和细胞外调节基质的机制的影响 沉积和降解，部分是通过激活基质金属蛋白酶(MMPs)和增强 转化生长因子-β信号传导。在此之前，该实验室确定膜结合的1型基质金属蛋白酶(MT1-基质金属蛋白酶)是关键 TAA形成的中介物通过激活基质金属蛋白酶-2在细胞外和细胞内的蛋白分解作用 转化生长因子-β信号传导。此外，我们还证明了MT1-基质金属蛋白酶的磷酸化可以调节酶的功能 通过改变其细胞位置，从而调节对特定底物的访问，改变其在细胞外基质重塑中的作用 和TAA的整体进展。尽管我们对TAA的病理生物学的了解有所进步，但这些 创新尚未转化为TAA的筛查、诊断、跟踪和治疗的发展。 因此，迫切需要不仅确定治疗靶点，而且开发非侵入性方法。 用于早期发现TAA先于危及生命的主动脉并发症。我们实验室和其他机构的工作 已证实特定的MMPs及其内源性抑制物(TIMPs)参与了发病机制 TAA的研究结果，类似的发现已经在microRNAs中得到证实。我们实验室的初步数据显示 确定了这些MMPs、TIMP和microRNAs可以在血浆中直接定量，并且水平可以 潜在地用于筛选TAA患者的存在和病因亚型的算法。 然而，关于这些分析物在遗传触发的个体中的循环水平，我们知之甚少。 TAA。重要的是，已建立的遗传引发的主动脉畸形的全面生物谱系信息库- Rysms和心血管状况(GenTAC)由收集的主动脉组织和血浆样本组成 来自与TAA有关的多个共同倾向的个体。因此，我们建议调查UTI- 利用这一资源，为不同亚型的TAA得出新的治疗和诊断策略。一致同意- 同样，这一建议的中心假设是MT1-MMPs的功能在不同的病因中发生改变。 TAA的亚型，这些亚型可以通过不同的MMP、TIMP和 MicroRNAs，将通过以下具体目标进行审查：(1)展示不同的作用 MT1-基质金属蛋白酶在遗传触发的胸主动脉瘤中的作用，以及(2)证实了先前发现的血浆 遗传易感性患者TAA鉴定的生物标志物组合。

PROJECT SUMMARY: Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling of the aortic extracellular matrix (ECM). This process weakens the aortic wall and leads to gross dilation that typically progresses to rupture in a generally asymptomatic way. There are several well described etiologies that contribute to the formation and progression of TAA. These include genetic syndromes, as well as, non-syndromic inheritable predispositions. Current treatment options are limited and consist of surgical reconstruction or endo- vascular intervention; neither of which address the underlying mechanisms responsible for disease. It is well described that TAAs are influenced by both intra- and extra- cellular mechanisms that function to regulate matrix deposition and degradation, in part, through activation of the matrix metalloproteinases (MMPs) and enhanced TGF-β signaling. Previously, this laboratory identified the membrane-bound type-1 MMP (MT1-MMP) as a key mediator of TAA formation through its role in both pericellular proteolysis by activation of MMP-2 and intracellular TGF-β signaling. Furthermore, we demonstrated that phosphorylation of MT1-MMP regulates enzymatic function by altering its cellular location, thus mediating access to specific substrates, shifting its role in ECM remodeling and overall progression of TAA. Despite advancements in our understanding of the pathobiology of TAA, these innovations have yet to be translated into development of screening, diagnosis, tracking, and treatment of TAA. Therefore, there is an urgent need to not only identify therapeutic targets, but also develop non-invasive methods for the early detection of TAA preceding life threatening aortic complications. Work from our laboratory and others have confirmed that specific MMPs, and their endogenous inhibitors (TIMPs) are implicated in the pathogenesis of TAA, and similar findings have been demonstrated with microRNAs. Preliminary data from our laboratory has established that theses MMPs, TIMPs, and microRNAs can be directly quantitated in plasma, and levels can be potentially utilized in an algorithm for screening patients for both the presence and etiological subtype of TAA. However, little is known in regards to circulating levels of these analytes in individuals with genetically triggered TAA. Importantly, the established comprehensive biospecimen repository of Genetically Triggered Aortic Aneu- rysms and Cardiovascular Conditions (GenTAC) is composed of aortic tissue and plasma specimens collected from individuals of multiple common predispositions linked to TAA. Therefore, we propose an investigation uti- lizing this resource to derive novel therapeutic and diagnostic strategies for different subtypes of TAA. Accord- ingly, the central hypotheses of this proposal are that the function of MT1-MMP is altered in different etiological subtypes of TAA, and these subtypes are distinguishable by a distinct plasma profile of MMPs, TIMPs, and microRNAs, which will be examined through the following specific aims: (1) Demonstrate a differential role of MT1-MMP in genetically triggered thoracic aortic aneurysms, and (2) Confirm a previously identified plasma biomarker panel for identification of TAA in patients with genetic predisposition.