Extracellular Matrix Metabolism in Thoracic Aortic Aneurysm and Dissection

胸主动脉瘤和夹层的细胞外基质代谢

• 批准号: 7904926
• 负责人: SCOTT A LEMAIRE
• 金额: $ 38.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904926
• 关键词: Aneurysm; Animal Model; Animals; Aorta; Aortic Aneurysm; Blood Vessels; Cell Culture Techniques; Cells; Clinical; Clinical Treatment; Collagen; Coronary Arteriosclerosis; Defect; Development; Digestion; Disease; Dissection; Doctor of Medicine; Doctor of Philosophy; Elastin; Environmental Exposure; Environmental Risk Factor; Enzymes; Equilibrium; Experimental Designs; Exposure to; Extracellular Matrix; Extracellular Matrix Degradation; Fibroblasts; Future; Genes; Health; In Vitro; Individual; Inflammation; Knockout Mice; Lead; Marfan Syndrome; Matrix Metalloproteinases; Measures; Medial; Medical; Metabolism; Modeling; Mutation; Natural regeneration; Operative Surgical Procedures; Patients; Peptide Hydrolases; Pharmacologic Substance; Physiological Processes; Population; Population Study; Predisposition; Prevention; Process; Procollagen-Proline Dioxygenase; Production; Research; Research Personnel; Resistance; Role; Rupture; Sampling; Smooth Muscle Myocytes; Structure; TNF gene; Testing; Thoracic Aortic Aneurysm; Transgenic Mice; Transgenic Model; Vascular Diseases; Wild Type Mouse; cigarette smoking; clinical practice; evidence base; experience; improved; in vitro Model; in vivo; knockout gene; mortality; mouse model; novel; overexpression; programs; repaired; response; sample collection; tool

DESCRIPTION (provided by applicant): Although thoracic aortic aneurysm and dissection (TAAD) are not as common as some forms of vascular diseases, e.g. coronary artery disease, it is a clinically insidious disease with high fatality. If untreated, rupture occurs in 70% of patients resulting in a 94% mortality rate, which makes it a high impact health problem at both population and individual levels. Appropriate surgical therapy dramatically improves long-term survival. However, when and how to treat these patients is still experience- rather than evidence-based clinical practice. TAAD will occur in an aorta if one or more of the following conditions are present: 1) original aortic structure is too weak; 2) destructive forces are too powerful; 3) repair mechanisms are not competent. While all three aspects are critical in the disease development, the central hypothesis to be tested in this project is that extracellular matrix (ECM) production and organization in aortic wall determine how aorta will respond to inadequate matrix protease activation, hence formation of aneurysm or dissection. We have developed four Specific Aims: (1) To investigate the role of ECM metabolism in patients with TAAD. We will examine qualitatively and quantitatively the collagen and elastin, enzymes involved in collagen and elastin synthesis and secretion, and degradation in aortic samples of TAAD patients and compare with normal aortas. (2) To examine the hypothesis that ECM production capacity by aortic smooth muscle cells (SMCs) may be compromised in TAAD patients. We will use in vitro model by culturing aortic SMCs from TAAD patients and comparing with SMCs of normal aortas. (3) To examine the role aortic adventitial fibroblasts in ECM production in aortas from normal control and TAAD patients. In addition to resident medial layer SMCs, adventitial fibroblasts may either migrate to medial layer or stay in adventitial layer and contribute to the overall ECM metabolism. We will follow the same experimental design as those in the Aim 2 and evaluate the potential differences in fibroblasts collected from normal and TAAD aortas. (4) To evaluate the involvement of arterial wall ECM production in aneurysm development in vivo. To provide evidence for the causal relationship between the ECM production and aneurysm-like changes in aortic wall, we will use single gene knockout or transgenic mouse models and measure the impact on quantitative changes in aortic wall. We will regenerate TAAD by local CaCl2 challenge, which activates matrix metalloproteinases (MMPs) and causes aortic aneurysms. Our current project will investigate this novel hypothesis that ECM production determines the susceptibility to TAAD development, in vivo (patient study and animal model) and in vitro (cell culture model). Our project will lead to the establishment of evidence-based guides for surgical and/or medical treatments of TAAD. With our unique access to a large number of TAAD patients and expertise in cell and animal models, our project is feasible.

描述(申请人提供)：虽然胸主动脉瘤和夹层(TAAD)不像某些形式的血管疾病，如冠状动脉疾病那样常见，但它是一种临床潜伏性疾病，具有很高的病死率。如果不治疗，70%的患者会发生破裂，导致94%的死亡率，这使其成为对人群和个人都有很大影响的健康问题。适当的手术治疗显著提高了长期存活率。然而，何时以及如何治疗这些患者仍然是经验而不是循证的临床实践。如果出现以下一种或多种情况，就会发生主动脉TAAD：1)原始的主动脉结构太弱；2)破坏力太强；3)修复机制不起作用。虽然这三个方面在疾病的发展过程中都是关键的，但这个项目要检验的中心假设是，主动脉壁细胞外基质(ECM)的产生和组织决定了主动脉对基质酶激活不足的反应，从而形成动脉瘤或夹层。我们制定了四个具体目标：(1)研究细胞外基质代谢在TAAD患者中的作用。我们将定性和定量地检测TAAD患者主动脉标本中胶原和弹性蛋白、参与胶原和弹性蛋白合成和分泌的酶以及降解情况，并与正常主动脉进行比较。(2)探讨TAAD患者主动脉平滑肌细胞(SMCs)分泌ECM能力受损的假说。我们将通过培养TAAD患者的主动脉SMCs并与正常主动脉的SMC进行比较，建立体外模型。(3)检测正常对照组和TAAD患者主动脉外膜成纤维细胞在ECM生成中的作用。外膜成纤维细胞除了存在于中层外，还可迁移至中层或停留在外膜，参与细胞外基质的整体代谢。我们将遵循与目标2相同的实验设计，并评估从正常和TAAD主动脉收集的成纤维细胞的潜在差异。(4)探讨动脉壁细胞外基质的产生在体内动脉瘤形成中的作用。为了证明细胞外基质的产生与主动脉壁瘤样变之间的因果关系，我们将使用单基因敲除或转基因小鼠模型，并测量其对主动脉壁数量变化的影响。我们将通过局部CaCl2刺激来再生TAAD，这会激活基质金属蛋白酶(MMPs)并导致主动脉瘤。我们目前的项目将在体内(患者研究和动物模型)和体外(细胞培养模型)研究这一新的假设，即ECM的产生决定了TAAD的易感性。我们的项目将导致为TAAD的外科和/或内科治疗建立循证指南。凭借我们接触大量TAAD患者的独特途径以及细胞和动物模型方面的专业知识，我们的项目是可行的。