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

基本信息

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
项目类别：
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

项目摘要

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（TAAD）是多种危及生命的表现。血管平滑肌细胞（VSMC）或细胞外基质（ECM）疾病的组织病理学标志。 TAAD是主动脉内侧变性（AMD），特点是蛋白多糖堆积（池化）、弹性纤维碎裂和 VSMC 变性会改变主动脉生物力学并促进解剖。通过提高主动脉壁内的局部组织肿胀压力但其精确性被忽视了。其成分、其细胞影响以及作为治疗靶点的潜力尚未被探索。大聚集蛋白聚糖聚集蛋白聚糖和多功能蛋白聚糖的积累是一致的病理特征 TAAD 的作用，改变 VSMC 表型和生存，从而损害主动脉功能，可能是由于减少我们会问：聚集蛋白聚糖和多功能蛋白聚糖的积累是人类 TAAD 的一致特征吗？无论主要原因如何，它们是疾病严重程度的指标吗？它们的积累是由什么引起的？除了 mRNA 上调（例如 TGFβ 失调后）外，ADAMTS 蛋白酶活性也降低， TAAD 中常见的蛋白聚糖池还有哪些成分？聚集蛋白聚糖和多功能蛋白聚糖的积累对 VSMC 有何影响？它们的减少会预防或改善 TAAD 吗？通过串联质谱法对正常人主动脉和 TAAD 主动脉进行蛋白多糖分析，鉴定出 20 蛋白聚糖，包括长期以来被认为是重要血管成分的多功能蛋白聚糖和聚集蛋白聚糖，传统上被视为正常和 TAAD 上行的软骨和神经成分。在克利夫兰诊所前瞻性收集的主动脉显示聚集蛋白聚糖出现意外的大量增加在马凡综合征小鼠模型中，TAAD 主动脉中聚集蛋白聚糖和多能聚糖均在 TAA 中积累。小鼠中聚集蛋白聚糖和多功能蛋白聚糖单倍体的聚集蛋白聚糖/多功能蛋白聚糖降解蛋白酶 ADAMTS1 不足。具体目标是： 1. 使用定量方法表征人类 TAAD 中的蛋白聚糖失调。串联质谱法并研究其与疾病严重程度的相关性 2. 确定。 ADAMTS1 减少蛋白多糖周转导致 TAAD 的致病机制过量的聚集蛋白聚糖对VSMC功能的影响3.测试聚集蛋白聚糖和/或多功能蛋白聚糖是否基因缺失。防止马凡综合征小鼠模型和 Adamts1 单倍剂量不足的小鼠中的 TAA 和/或解剖。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之外，工作将确定主动脉壁易发生动脉瘤和/或夹层的机制，提供新的治疗方法用于诊断和监测 TAAD 的生物标志物，并确定可针对非手术治疗的途径 TAAD 的管理。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exosites in Hypervariable Loops of ADAMTS Spacer Domains control Substrate Recognition and Proteolysis.

ADAMTS 间隔域超变环中的外位点控制底物识别和蛋白水解。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Santamaria, Salvatore;Yamamoto, Kazuhiro;Teraz;Koch, Christopher;Apte, Suneel S;de Groot, Rens;Lane, David A;Ahnström, Josefin
通讯作者：
Ahnström, Josefin