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.

胸主动脉瘤和夹层（TAAD）是一种危及生命的表现， 血管平滑肌细胞（VSMC）或细胞外基质（ECM）疾病。组织病理学特征 TAAD是主动脉中层变性（AMD），其特征在于蛋白多糖积聚（汇集）、弹性纤维变性（弹力纤维变性）、血管变性（血管变性）和血管变性。 细胞碎片化和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的局部组织肿胀压力，但被忽略。它们的精确 然而，由于它们的组成，它们的细胞影响和作为治疗靶点的潜力尚未被探索。我们假设 聚集蛋白聚糖聚集蛋白聚糖和多功能蛋白聚糖的大量聚集是一个一致的病理特征 TAAD改变了VSMC表型和存活率，从而损害主动脉功能，并且可能由TAAD的减少引起。 蛋白水解我们会问：聚集蛋白聚糖和多功能蛋白聚糖的积累是人类TAAD的一个一致特征吗 不管主要原因是什么，它们是疾病严重程度的指标吗？它们的积累是否源于 ADAMTS蛋白酶活性降低以及mRNA上调，如TGFβ失调后， 常见于TAAD？AMD中蛋白聚糖池的其他成分是什么？什么影响 聚集蛋白聚糖和多功能蛋白聚糖的积累对VSMC的影响？它们的减少会预防或改善TAAD吗？ 通过串联质谱法鉴定了正常人主动脉和TAAD主动脉的蛋白聚糖谱20 蛋白聚糖，包括多能蛋白聚糖，长期以来已知是重要的血管成分，和聚集蛋白聚糖， 传统上被认为是软骨和神经成分。正常和TAAD上升的免疫染色 在克利夫兰诊所前瞻性收集的样本显示聚集蛋白聚糖的意外大量增加， 和多功能的在马凡氏综合征小鼠模型中，聚集蛋白聚糖在TAA中积累， 聚集蛋白聚糖和多功能蛋白聚糖在小鼠中的单倍不足的聚集蛋白聚糖/多功能蛋白聚糖降解蛋白酶，ADAMTS 1。 具体目标是：1.使用定量方法表征人TAAD中的蛋白聚糖失调 串联质谱方法并研究其与疾病严重程度的相关性。2.确定 ADAMTS 1降低蛋白聚糖周转导致TAAD的致病机制， 过量聚集蛋白聚糖对VSMC功能影响。3.为了测试聚集蛋白聚糖和/或多功能蛋白聚糖的基因缺失是否 预防马凡氏综合征和Adamts 1-单倍不足小鼠模型中的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， 这项工作将确定使主动脉壁易患动脉瘤和/或夹层的机制， 用于诊断和监测TAAD的生物标志物，并确定非手术治疗的靶向途径。 TAAD的管理。