PATHOLOGICAL CONSEQUENCES OF THE PLASMINOGEN SYSTEM

纤溶酶原系统的病理后果

• 批准号: 6530721
• 负责人: Victoria Ploplis
• 金额: $ 25.37万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530721
• 关键词: atherosclerosis; cell migration; extracellular matrix; gene targeting; genetically modified animals; histology; immunocytochemistry; inflammation; laboratory mouse; metalloendopeptidases; molecular pathology; plasminogen; protein degradation; pulmonary fibrosis /granuloma; vascular endothelium permeability

The long-term goal of this proposal is to test hypothesized functions of the plasminogen system in defined physiological and pathological processes utilizing gene knock-out mice and to identify previously unrecognized functions of this system. The contribution of the plasminogen system in hemostasis, through plasmin's ability to directly degrade fibrin, has been extensively analyzed and is well accepted. The identification of receptors for components of the plasminogen system on a number of cell surfaces implicates plasmin in playing a role in cell migratory events such as the inflammatory response. Paramount to this response and other cell migratory events is the degradation of extracellular matrix. Plasmin is believed to play a major role in this process either directly or through activation of other matrix degrading proteins, i.e., metalloproteases. The inflammatory response is associated with the early stages of a number of pathologies, such as pulmonary fibrosis and atheroscelerosis and regulation of these early events may dictate the clinical outcome of these diseases. The availability of gene knock-out mice to all components of the plasminogen system offers an unique opportunity to analyze, in vivo, in a mechanistic fashion its function in these pathologies. In this study mice deficient for components of the plasminogen system will be challenged utilizing two models of inflammatory diseases, pulmonary fibrosis and atherosclerosis. The effect components of the plasminogen system has on events associated with both early inflammatory response and later stages of these diseases will be investigated. Utilizing these gene knock-out mice, this proposal will specifically: (1) study bleomycin induced pulmonary fibrosis by assessing early inflammatory events; alterations in the integrity of the capillary/alveolar wall integrity; lesion development; and metalloprotease involvement. (2) study copper cuff induced atherosclerosis by determine qualitative and quantitative changes in the vessel wall and lumen utilizing a battery of histological and immunohistological techniques.

本提案的长期目标是利用基因敲除小鼠在确定的生理和病理过程中测试纤溶酶原系统的假设功能，并鉴定该系统以前未被识别的功能。 纤溶酶原系统通过纤溶酶直接降解纤维蛋白的能力在止血中的作用已被广泛分析并被广泛接受。 许多细胞表面上纤溶酶原系统组分的受体的鉴定暗示纤溶酶在细胞迁移事件如炎症反应中起作用。 对这种反应和其他细胞迁移事件至关重要的是细胞外基质的降解。 纤溶酶被认为在该过程中直接或通过激活其它基质降解蛋白，即，金属蛋白酶 炎症反应与许多病理学的早期阶段相关，例如肺纤维化和动脉粥样硬化，并且这些早期事件的调节可能决定这些疾病的临床结果。 基因敲除小鼠对纤溶酶原系统的所有组分的可用性提供了一个独特的机会，以在体内以机械方式分析其在这些病理中的功能。在这项研究中，将利用两种炎性疾病模型，肺纤维化和动脉粥样硬化，对缺乏纤溶酶原系统组分的小鼠进行攻击。 将研究纤溶酶原系统对与这些疾病的早期炎症反应和后期阶段相关的事件的影响。 利用这些基因敲除小鼠，该提议将具体地：（1）通过评估早期炎症事件、毛细血管/肺泡壁完整性的改变、病变发展和金属蛋白酶参与来研究博来霉素诱导的肺纤维化。 (2)应用组织学和免疫组化技术，通过测定血管壁和管腔的定性和定量变化，研究铜套引起的动脉粥样硬化。