PLASMIN, FIBRIN, AND METALLOPROTEINASES IN LUNG FIBROSIS

肺纤维化中的纤溶酶、纤维蛋白和金属蛋白酶

• 批准号: 6642103
• 负责人: THOMAS H SISSON
• 金额: $ 13.34万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-20 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642103
• 关键词: Adenoviridae; bleomycin; disease /disorder model; fibrin; gene targeting; genetically modified animals; laboratory mouse; metalloendopeptidases; model design /development; plasmin; plasminogen activator; pulmonary fibrosis /granuloma

The outlined proposal is designed as a training program that builds on prior experiences and ultimately leads to a career of independent research. Included in this program for the applicant is the introduction of new experimental techniques, investigation of a new area of basic science, and interaction with a new mentor. The research project will investigate an important aspect of the development of pulmonary fibrosis. Pulmonary fibrosis has been shown to occur in conjunction with depressed alveolar plasminogen activator activity. This impaired activity occurs from an imbalance between urokinase-type plasminogen activator (uPA) and its major inhibitor, plasminogen activator inhibitor-1 (PAI-1). Enhancing alveolar plasminogen activator activity through various means including targeted deletion of the PAI-1 gene or adenoviral-mediated gene transfer of the uPA cDNA results in decreased collagen accumulation following a fibrogenic insult. The mechanism by which enhanced alveolar plaminogen activator activity mitigates fibrosis is unknown. Insights into this mechanism may lead to new treatments. Of several possibilities, two mechanisms are most likely. The hypothesis of this proposal is that enhanced alveolar plasminogen activator activity may reduce fibrosis by removing the provisional fibrin matrix or by increased levels of matrix metalloproteinases (MMPs). To test this hypothesis, 3 models of enhanced alveolar plasminogen activator activity will be employed. These models include a PAI-1 deficient transgenic mouse, adenoviral-mediated gene transfer of the uPA cDNA to the alveolar space, and an inducible lung-specific uPA expressing transgenic mouse. In addition, to investigate the importance of fibrin in lung scarring, a fibrinogen deficient transgenic mouse will be employed. With these models, differences in fibrin accumulation and MMP activation in mice protected from fibrosis will be compared to susceptible controls. The opportunities provided by the training program will provide the foundation for career advancement and hopefully lead to new therapies for fibrotic lung diseases.

概述的提案被设计为一项培训计划，该计划以先前的经验为基础，并最终导致独立研究的职业。 该计划中的申请人包括引入新的实验技术，对新的基础科学领域的调查以及与新导师的互动。 该研究项目将研究肺纤维化发展的重要方面。 肺纤维化已显示出与降低肺泡纤溶酶原激活剂活性结合发生的。 这种受损的活性是由于尿激酶型纤溶酶原激活剂（UPA）及其主要抑制剂纤溶酶原激活剂抑制剂1（PAI-1）之间的不平衡发生。 通过各种手段增强肺泡纤溶酶原活化剂活性，包括对PAI-1基因的靶向缺失或UPA cDNA的腺病毒介导的基因转移导致纤维化损伤后胶原蛋白的积累降低。 增强的肺泡质质激活剂活性减轻纤维化的机制尚不清楚。 对这种机制的见解可能会导致新的治疗方法。 在几种可能性中，很可能有两种机制。 该提议的假设是，增强的肺泡纤溶酶原激活剂活性可以通过去除临时纤维蛋白基质或通过增加的基质金属蛋白酶（MMP）来降低纤维化。 为了检验这一假设，将采用3种增强的肺泡纤溶酶原活化剂活性的模型。 这些模型包括PAI-1不足的转基因小鼠，UPA cDNA向肺泡空间的腺病毒介导的基因转移以及诱导的肺特异性UPA表达转基因小鼠。 此外，为了研究纤维蛋白在肺疤痕中的重要性，将采用纤维蛋白原缺乏的转基因小鼠。 对于这些模型，将将免于纤维化的小鼠的纤维蛋白积累和MMP激活的差异与易感对照进行比较。 培训计划提供的机会将为职业发展提供基础，并希望为纤维化肺部疾病提供新的疗法。