Enhanced Biochemical Monitoring for Aortic Aneurysm Disease

加强主动脉瘤疾病的生化监测

• 批准号: 10716621
• 负责人: Adam William Akerman
• 金额: $ 69.61万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716621
• 关键词: Advanced Development; Algorithms; Aneurysm; Aorta; Aortic Aneurysm; Aortic Rupture; Award; Basic Science; Biochemical; Biological Assay; Biological Markers; Blood; Blood Tests; Blood Vessels; Blood specimen; Cardiovascular system; Cause of Death; Cell Communication; Cells; Charge; Clinical; Collagen; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Diameter; Disease; Disease Progression; Dissection; Early Diagnosis; Early identification; Elastin; Elderly; Elements; Enzymes; Epidemiologist; Equipment; Etiology; Evaluation; Exposure to; Extracellular Matrix; General Population; Geography; Growth; Hospitals; Human; Image; Imaging Techniques; Laboratories; Life; Location; Magnetic Resonance Imaging; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediator; Methods; MicroRNAs; Molecular Sieve Chromatography; Monitor; Morbidity - disease rate; Operative Surgical Procedures; Pathologic; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Persons; Physiologic pulse; Pilot Projects; Plasma; Play; Predictive Value; Process; Proteolysis; Radiation; Reproducibility; Resources; Risk; Risk Assessment; Rupture; Sampling Studies; Scientist; Severities; Signal Pathway; Specificity; Standardization; Stress; Structure; Surface; Surgeon; Suspensions; Symptoms; Techniques; Technology; Testing; Thoracic Aortic Aneurysm; Tissue Inhibitor of Metalloproteinases; Tissues; Transforming Growth Factor beta; Translating; Translational Research; Translations; United States; Untranslated RNA; X-Ray Computed Tomography; access disparities; biobank; circulating microRNA; classification trees; clinical diagnostics; cost; cost efficient; diagnostic assay; diagnostic tool; digital; disenfranchised population; economic disparity; exosome; experimental study; extracellular vesicles; health care availability; health equity; insight; instrument; marginalized community; microvesicles; mortality; novel; novel diagnostics; nucleic acid detection; point of care; point-of-care diagnostics; regression trees; repository; risk stratification; screening

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.

项目摘要 主动脉瘤（AA）是美国发病率和死亡率的主要原因， 对于心血管外科医生来说是一个棘手的管理问题。这种疾病削弱了血管壁， 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 疾病高度依赖于昂贵的先进成像技术，如计算机断层扫描（CT）， 磁共振成像（MRI）。目前还没有即时血浆生物标志物测定， 筛查AA或跟踪疾病进展，以告知手术干预的最佳时机。发展 能够诊断、定位、跟踪和评估AA直径（或风险）的新型检测方法： 组装了一个广泛的临床血浆生物储存库和选定的仪器，这些仪器是定量的，可扩展的， 可重复，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 检验动脉瘤生物标志物的定量能够增强AA的生化监测的假设。 在动脉瘤组织中，增强的蛋白水解导致病理性重塑和进行性扩张。这 通常持久的基质分子，如弹性蛋白和胶原蛋白的分解，强调了参与 基质金属蛋白酶（MMPs）及其内源性调节因子，基质金属蛋白酶组织抑制剂 金属蛋白酶（TIMPs）。这些酶降解血管壁的所有成分，并归因于 动脉瘤疾病的发展和进展。MicroRNA代表一类小的非编码RNA， 调节翻译，并且在AA进展期间由主动脉细胞分泌一个子集。细胞外囊泡 (EVs)已被鉴定为细胞间通讯和细胞外基质重塑的关键介质。 EV含有多种MMPs、TIMPs、microRNA和转化生长因子（TGF）-β，所有这些都影响着 信号通路，并有助于血管壁的降解。本实验室进行的实验 显示当动脉瘤出现时，一组独特的循环分子也会出现。这些签名 在AA位置、亚型和大小之间，概况是不同的。 因此，实验和测试将证明以下三个目标。首先，AA可以在 通过分析MMP：TIMP比率，因为它提供了主动脉内蛋白水解活性的独特度量， 墙第二，在应激下从主动脉细胞分泌的microRNA的子集与主动脉内皮细胞分泌的microRNA的子集线性相关。 AA的直径和病理进展。第三，循环细胞外囊泡（EV）的大小、结构和 在患有AA亚型的患者中，蛋白质组成发生改变，并且对它们进行分析构成诊断测定。 即使一个目标作为诊断检测失败，另一个目标也可以取代它;尽管如此，这项研究将 提供机制数据和深入了解参与AA进展的上游途径。综合来看，这项研究 将推进早期诊断和风险分层的标准化筛查试验的开发， 减轻危及生命的主动脉并发症。