Enhanced Biochemical Monitoring for Aortic Aneurysm Disease

项目总结 在美国，主动脉瘤(AA)是发病率和死亡率的主要原因，而且还在继续 对于心血管外科医生来说，这是一个棘手的管理问题。这种疾病削弱了血管壁和 导致扩张，在没有症状的情况下可能进展为破裂。目前，动脉瘤的诊断 疾病高度依赖昂贵的先进成像技术，如计算机断层扫描(CT)和 磁共振成像(MRI)。目前还没有可用的护理点血浆生物标记物分析 要么筛查AAS，要么跟踪疾病进展，以告知手术干预的最佳时机。发展，发展 能够诊断、定位、跟踪和评估AAS直径(或风险)的新分析方法：我们有 组装了广泛的临床血浆生物信息库和精选的定量、可扩展、 可重复性，并且能够自动化。使用这个储存库，以及新收集的血液样本，我们将 对动脉瘤生物标记物的量化能够加强再生障碍性贫血生化监测的假设进行检验。 在动脉瘤中，组织蛋白降解增强导致病理性重塑和进行性扩张。这 通常持续时间较长的基质分子，如弹性蛋白和胶原蛋白的分解，强调了 基质金属蛋白酶及其内源性调节因子--基质组织抑制因子 金属蛋白酶(TIMPs)。这些酶降解血管壁的所有成分，并被归因于 动脉瘤病的发生和发展。MicroRNA代表一类小的非编码RNA，它 在AA的进展过程中，主动脉细胞分泌调节翻译和一个亚群。胞外小泡 血管内皮生长因子(EVS)是细胞间通讯和细胞外基质重塑的重要介质。 EV含有多个MMPs、TIMP、microRNAs和转化生长因子(TGF)，所有这些都会影响 信号通路和促进血管壁的降解。这个实验室进行的实验 表明当出现动脉瘤时，一组独特的循环分子也会出现。这些签名 配置文件在AA位置、亚型和大小之间是不同的。 相应地，实验和测试将证明以下三个目标。首先，可以在以下位置确定AA 通过分析基质金属蛋白酶：组织金属蛋白酶与基质金属蛋白酶的比值来测定血浆，因为它提供了主动脉内蛋白分解活性的唯一指标 墙。第二，应激状态下主动脉细胞分泌的microRNAs亚群与主动脉呈线性相关。 再生障碍性贫血的直径和病理进展。第三，循环细胞外小泡(EV)的大小、结构和 AA亚型患者的成分会发生变化，对它们进行分析构成了一种诊断分析。 即使一个目标作为诊断分析失败了，另一个目标可以取而代之；然而，这项研究将 提供机械数据和对AA进展中涉及的上游途径的洞察。总而言之，这项研究 将推动开发用于早期诊断和风险分层的标准化筛查方法，以 减少危及生命的大动脉并发症。

PROJECT SUMMARY Aortic Aneurysm (AA) represents a major cause of morbidity and mortality in the United States and continues to be a difficult management problem for cardiovascular surgeons. This disease weakens the vessel wall and leads to dilation that can progress to rupture in the absence of symptoms. At present, the diagnosis of aneurysm disease is highly dependent on costly, advanced imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). There are no point-of-care plasma biomarker assays currently available that either screen for AAs or follow disease progression to inform optimal timing for surgical intervention. To develop novel assays capable of diagnosing, locating, tracking, and assessing diameter (or risk) of AAs: We have assembled an extensive clinical plasma biorepository and selected instruments that are quantitative, scalable, reproducible, and able to be automated. Using this repository, as well as newly collected blood samples, we will test the hypothesis that quantification of aneurysm biomarkers enables enhanced biochemical monitoring for AA. In aneurysm tissue enhanced proteolysis results in pathological remodeling and progressive dilation. This breakdown of normally long-lasting matrix molecules, such as elastin and collagen, emphasizes the involvement of Matrix Metalloproteinases (MMPs), and their endogenous regulators, the Tissue Inhibitors of Matrix Metalloproteinases (TIMPs). These enzymes degrade all components of the vessel wall and are attributed to the development and progression of aneurysm disease. MicroRNAs represent a class of small non-coding RNA that regulate translation and a subset are secreted by aortic cells during progression of AA. Extracellular Vesicles (EVs) have been identified as critical mediators of cell-to-cell communication and extracellular matrix remodeling. EVs contain multiple MMPs, TIMPs, microRNAs, and the transforming growth factor (TGF)-ß, all which influence signaling pathways and contribute to degradation of the vascular wall. Experiments conducted by this laboratory show that when an aneurysm presents, a unique set of these circulating molecules also emerge. These signature profiles are different among AA location, subtype, and size. Accordingly, experiments and testing will demonstrate the following three aims. First, AA can be identified in plasma by profiling the MMP:TIMP ratio because it provides a unique metric of proteolytic activity within the aortic wall. Second, that the subset of microRNAs secreted from aortic cells under stress is correlated linearly to aortic diameter and pathological progression of AA. Third, circulating Extracellular Vesicle (EV) size, structure, and composition is altered in patients with AA subtypes and profiling them constitutes a diagnostic assay. Even if one aim should fail as a diagnostic assay, another can take its place; nevertheless, this study will provide mechanistic data and insight into upstream pathways involved in AA progression. Combined, this study will advance the development of a standardized screening assay for early diagnosis and risk stratification to mitigate life-threatening aortic complications.