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Pathological Consequences of the Plasminogen System

纤溶酶原系统的病理后果

基本信息

批准号：
7862315
负责人：
Victoria Ploplis
金额：
$ 37.5万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862315
关键词：
Affect Apoptosis Apoptotic Binding Biological Biology Blood capillaries Cardiac Carotid Arteries Caspase Cell Adhesion Cell Cycle Progression Cell Differentiation process Cell Proliferation Cell physiology Cell surface Cells Chronic Endothelial Cells Event Extracellular Matrix Extracellular Matrix Degradation Fibrin Fibrosis Funding Future Gene Targeting Genes Goals Grant Hemostatic function In Vitro Injury LDL-Receptor Related Protein 1 Laboratories Lipoprotein Receptor Mediating Metalloproteases Modeling Molecular Profiling Mus Mutation Nuclear Translocation Pathologic Processes Pathway interactions Phenotype Physiological Plasmin Plasminogen Plasminogen Activator Inhibitor 1 Play Process Proliferating Protein Binding Domain Protein Deficiency Proteins Pulmonary Fibrosis Recombinants Relative (related person)Role Signal Pathway Signal Transduction Skin Staging System Tube Urokinase Urokinase Plasminogen Activator Receptor Vitronectin Wound Healing angiogenesis base capillary cell motility in vivo in vivo Model inhibitor/antagonist migration mutant receptor tumor tumor growth

项目摘要

The long-term goal of this proposal is to identify functions and determine mechanisms of the fibrinolytic system, and its inhibitors, in physiological and pathological processes utilizing cell-based and in vivo models. The availability of mice with deficiencies of genes of the fibrinolytic system has resulted in direct analyses of the role of these proteins in a number of biological events. Studies have indicated that a PAI-1 deficiency diminishes angiogenesis in tumor models. Further, our laboratory has shown that endothelial cell (EC) signaling and function are regulated by PAI-1/LRP interactions. The current application will further elucidate effects of PAI-1 on cell signaling pathways and determine the importance of PAI-1/LRP interactions in both cellular and physiological events. As a result of these observations, the following studies are proposed: (1.) Determine the effects of a PAI-1 deficiency on murine EC JAK/STAT signaling and cell cycle progression. These studies will assess STAT and JAK expression profiles and activation status in proliferating wild-type (WT) and PAI-1-/- EC as well as the extent of nuclear translocation of STAT. The addition of rPAI-1 and mutants will determine which functional domains of PAI-1 regulate the activation status of this pathway. Additional studies will determine effects on cell migration. Downstream effects on cell cycle progression will also be investigated. The hypothesis is that a PAI-1 deficiency will affect JAK/STAT signaling and downstream cell cycle progression, and that these effects are mediated by PAI-1/LRP interactions. (2.) Characterize early and late stage events of cardiac fibrosis in PAI-1-/- and uPA-/-/PAI-1-/- mice. Recent studies have shown that PAI-1-/- mice develop cardiac fibrosis, which may be mediated by dysregulated uPA or chronic activation of the Akt pathway, the result of altered PAI-1/LRP interactions. The studies proposed will initially characterize cardiac fibrosis in PAI-1-/- and uPA-/-/PAI-1-/- mice in order to differentiate effects from uPA activity and PAI-1 functions independent of uPA inhibition in cardiac fibrosis phenotypes. The hypothesis is that cardiac fibrosis will be regulated by urokinase activity and other functions of PAI-I which will be further pursued in future studies of mice expressing functional mutations of PAI-1.

这一建议的长期目标是利用基于细胞的模型和体内模型来识别纤溶系统及其抑制物在生理和病理过程中的功能和机制。纤溶系统基因缺陷小鼠的出现导致了对这些蛋白质在许多生物事件中的作用的直接分析。研究表明，PAI-1缺乏会减少肿瘤模型中的血管生成。此外，我们的实验室已经证明，内皮细胞(EC)的信号和功能受PAI-1/LRP相互作用的调节。目前的应用将进一步阐明PAI-1对细胞信号通路的影响，并确定PAI-1/LRP相互作用在细胞和生理事件中的重要性。根据这些观察结果，建议进行以下研究： (1.)确定PAI-1缺乏对小鼠EC JAK/STAT信号和细胞周期进程的影响。这些研究将评估STAT和JAK在增殖野生型(WT)和PAI-1-/-EC中的表达谱和激活状态，以及STAT的核移位程度。RPAI-1和突变体的加入将决定PAI-1的哪些功能域调节这一途径的激活状态。其他研究将确定对细胞迁移的影响。下游对细胞周期进程的影响也将被调查。假设PAI-1缺乏将影响JAK/STAT信号和下游细胞周期进程，这些影响是由PAI-1/LRP相互作用介导的。 (2)描述PAI-1-/-和uPA-/-/PAI-1-/-小鼠心脏纤维化的早期和晚期事件。最近的研究表明，PAI-1-/-小鼠发生心脏纤维化，可能是由于PAI-1/LRP相互作用改变导致的uPA异常或Akt途径的慢性激活所致。拟议的研究将首先确定PAI-1-/-和uPA-//PAI-1-/-小鼠的心脏纤维化特征，以便区分uPA活性和PAI-1功能对心脏纤维化表型的影响，而不是抑制uPA。这一假说认为，心肌纤维化将受到PAI-I的尿激酶活性和其他功能的调节，这将在未来对表达PAI-1功能突变的小鼠的研究中进一步探索。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice.

因子 VII/蛋白 C 联合缺乏会导致小鼠宫内凝血病。

DOI：
10.1172/jci9095
发表时间：
2000
期刊：
The Journal of clinical investigation
影响因子：
0
作者：
Chan,JC;Cornelissen,I;Collen,D;Ploplis,VA;Castellino,FJ
通讯作者：
Castellino,FJ

Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1.

DOI：
发表时间：
2000-10
期刊：
Cancer research
影响因子：
11.2
作者：
L. Gutierrez;A. Schulman;Teresa Brito-Robinson;F. Noria;V. Ploplis;F. Castellino
通讯作者：
L. Gutierrez;A. Schulman;Teresa Brito-Robinson;F. Noria;V. Ploplis;F. Castellino

The fibrinolytic system in dissemination and matrix protein deposition during a mycobacterium infection.