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; 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）代表美国发病率和死亡率的主要原因，并继续 对于心血管外科医师来说，这是一个困难的管理问题。这种疾病削弱了容器壁和 导致词典在没有症状的情况下会破裂。目前，动脉瘤的诊断 疾病高度依赖于昂贵的高级成像技术，例如计算机断层扫描（CT）和 磁共振成像（MRI）。目前没有现有的水位等离子生物标志物测定 筛选AAS或遵循疾病进展，以告知最佳时机进行手术干预。发展 能够诊断，定位，跟踪和评估AAS直径（或风险）的新颖测定法：我们有 组装了广泛的临床等离子体生物座位和精选的仪器，可扩展，可扩展， 可重现，并且能够自动化。使用此存储库以及新收集的血液样本，我们将 检验以下假设：大量动脉瘤生物标志物可以增强对AA的生化监测。 在动脉瘤组织中，增强蛋白水解导致病理重塑和进行性扩张。这 正常持久基质分子（例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（MMP）及其内源性调节剂的组成剂，基质的组织抑制剂 金属蛋白酶（TIMP）。这些酶降解了容器壁的所有成分，并归因于 动脉瘤疾病的发展和进展。 microRNA代表一类小型非编码RNA 调节翻译和子集在AA进展过程中由主动脉细胞分泌。细胞外囊泡 （EV）已被确定为细胞间通信和细胞外基质重塑的关键介体。 电动汽车包含多个MMP，TIMP，microRNA和转化生长因子（TGF）-ß，所有这些都会影响 信号通路并导致血管壁降解。该实验室进行的实验 表明当动脉瘤呈现时，这些循环分子的独特集也出现。这些签名 AA位置，亚型和大小之间的轮廓不同。 彼此之间，实验和测试将证明以下三个目标。首先，可以在 血浆通过分析MMP：TIMP比率，因为它在主动脉内提供了独特的蛋白水解活性度量 墙。其次，在压力下从主动脉细胞分泌的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 AA亚型和分析的患者的组成改变构成诊断测定。 即使一个目标应该作为诊断测定法失败，另一个目标也可以代替。但是，这项研究将 提供机械数据并了解与AA进展有关的上游途径。合并，这项研究 将推进对早期诊断和风险分层的标准化筛选测定的开发 减轻威胁生命的主动脉并发症。