Proteoglycan dynamics in pathogenesis of thoracic aortic aneurysm and dissection

胸主动脉瘤和夹层发病机制中的蛋白多糖动力学

• 批准号: 9769293
• 负责人: SUNEEL S APTE
• 金额: $ 40万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769293
• 关键词: ADAMTS; ADAMTS1 gene; Adhesions; Adhesives; Affect; Age; Aneurysm; Aorta; Aortic Diseases; Area; Biological Markers; Biomechanics; Blood; Blood Circulation; Blood Vessels; Carbohydrates; Cartilage; Cell Adhesion; Cell Shape; Cell physiology; Cells; Chondroitin Sulfates; Cleaved cell; Clinic; Clinical; Collagen; Cytoskeleton; Data; Defect; Diagnosis; Disease; Dissection; Elastic Fiber; Elastin; Enzymes; Extracellular Matrix; FBN1; Functional disorder; Genes; Genetic; Hand; Health; Histology; Homeostasis; Human; Hyaluronan; Impairment; Individual; Knowledge; Left; Life; Maintenance; Marfan Syndrome; Mechanics; Medial; Mediating; Messenger RNA; Modeling; Monitor; Mus; Mutate; Names; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patient-Focused Outcomes; Peptide Hydrolases; Phenotype; Process; Property; Proteins; Proteoglycan; Proteolysis; Research; Resistance; Role; Scientist; Severity of illness; Shapes; Site; Smooth Muscle Myocytes; Stains; Stress Fibers; Structure; Surgeon; Swelling; Testing; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; Tunica Media; Up-Regulation; Vascular Smooth Muscle; Work; aggrecan; ascending aorta; base; biomedical referral center; cell dedifferentiation; extracellular; improved outcome; insight; interstitial; knock-down; mechanotransduction; mouse model; neglect; non-genetic; novel; novel marker; potential biomarker; pressure; prevent; prospective; relating to nervous system; response; tandem mass spectrometry; targeted treatment; treatment center; versican

SUMMARY: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening manifestation of diverse vascular smooth muscle cell (VSMC) or extracellular matrix (ECM) disorders. The histopathological hallmark of TAAD is aortic medial degeneration (AMD), characterized by proteoglycan accumulation (pooling), elastic fiber fragmentation and VSMC degeneration. Proteoglycan pools alter aorta biomechanics and facilitate dissection by raising focal tissue swelling pressure within the aortic wall but have been neglected. Their precise composition, their cellular impact and potential as a target for therapy are unexplored. We hypothesize that accumulation of the large aggregating proteoglycans aggrecan and versican is a consistent pathologic feature of TAAD, alters VSMC phenotype and survival to compromise aorta function, and could arise from reduced proteolysis. We will ask: Is aggrecan and versican accumulation a consistent feature of human TAAD regardless of primary cause, and are they indicators of disease severity? Does their accumulation result from reduced ADAMTS protease activity in addition to mRNA upregulation such as following TGFβ dysregulation, commonly seen in TAAD? What are other components of the proteoglycan pools in AMD? What impact does aggrecan and versican accumulation have on VSMC? Would their reduction prevent or ameliorate TAAD? Proteoglycan profiling of the normal human aorta and TAAD aorta by tandem mass spectrometry identified 20 proteoglycans, including versican, long known to be an important vascular component, and aggrecan, traditionally regarded as a cartilage and neural component. Immunostaining of normal and TAAD ascending aortas collected prospectively at the Cleveland Clinic revealed an unexpected, massive increase of aggrecan and versican in TAAD aortas. Aggrecan accumulated in TAA in a mouse model of Marfan syndrome, and both aggrecan and versican in mice haploinsufficient for the aggrecan/versican degrading protease, ADAMTS1. The specific aims are: 1. To characterize proteoglycan dysregulation in human TAAD using quantitative tandem mass spectrometry approaches and investigate its correlation to disease severity. 2. To determine the pathogenic mechanisms by which reduced proteoglycan turnover by ADAMTS1 contributes to TAAD and the impact of excess aggrecan on VSMC function. 3. To test whether genetic deletion of aggrecan and/or versican prevents TAA and/or dissection in mouse models of Marfan syndrome and Adamts1-haploinsufficient mice. Impact: In addition to new fundamental knowledge of aortic ECM dynamics and cell-matrix interactions, the work will identify mechanisms that predispose the aortic wall to aneurysms and/or dissection, provide novel biomarkers for diagnosis and monitoring of TAAD, and identify pathways that could be targeted in non-surgical management of TAAD.

摘要：胸主动脉瘤和夹层动脉瘤(Taad)是一种危及生命的多种疾病。 血管平滑肌细胞(VSMC)或细胞外基质(ECM)紊乱其组织病理学特征是 TAAD是一种主动脉中层变性(AMD)，其特征是蛋白多糖积聚(积聚)、弹性纤维 碎裂和VSMC变性。蛋白聚糖池改变主动脉生物力学并促进夹层 通过提高主动脉壁内局部组织的肿胀压力而被忽视。他们的精确度 它们的成分、细胞影响和作为治疗靶点的潜力尚未被探索。我们假设 聚集在一起的大聚集性蛋白多糖、琼脂多聚糖和多聚多糖是一贯的病理特征。 在TAAD中，改变VSMC的表型和存活率以损害主动脉功能，并可能由减少引起 蛋白质分解。我们会问：聚集性和多样性的积累是人类TAAD的一贯特征吗？ 不管主要原因是什么，它们是疾病严重程度的指标吗？他们的积累是不是源于 在转化生长因子β失调后，除基因表达上调外，ADAMTS蛋白酶活性降低； 在TAAD中常见吗？AMD中蛋白多糖池的其他成分是什么？会有什么影响？ 聚乙二醇胺和聚维酮对VSMC有何影响？他们的减少会阻止或改善TAAD吗？ 串联质谱法分析正常人和TAAD主动脉的蛋白质多聚糖图谱 蛋白多糖，包括多聚糖，长期以来被认为是重要的血管成分，以及聚集素， 传统上被认为是软骨和神经的组成部分。正常和TAAD升行期的免疫组化染色 克利夫兰诊所前瞻性收集的主动脉显示聚集性蛋白聚糖意外大幅增加 在TAAD的大动脉中也是如此。在马凡氏综合症小鼠模型中，聚集素在TAA中积聚，并且两者 聚集素/聚糖酶降解酶ADAMTS1在小鼠中单倍性缺乏聚集素和杂蛋白。 本研究的具体目的是：1.定量研究人TAAD中蛋白多糖的异常 串联质谱学方法，并研究其与疾病严重性的相关性。2.确定 ADAMTS1蛋白多糖周转减少在TAAD发病机制中的作用 过量聚集素对VSMC功能的影响。3.检测aggrecan和/或verscan的基因缺失 预防马凡综合征和ADAMTS1单倍体缺陷小鼠模型的TAA和/或夹层。 影响：除了主动脉ECM动力学和细胞-基质相互作用的新基础知识外， 工作将确定使主动脉壁易患动脉瘤和/或夹层的机制，提供新的 用于诊断和监测TAAD的生物标志物，并确定可作为非手术治疗靶点的途径 TAAD的管理。