Proteomic Analysis of Plasminogen Receptors

纤溶酶原受体的蛋白质组学分析

• 批准号: 7589725
• 负责人: Lindsey A Miles
• 金额: $ 47.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589725
• 关键词: Accounting; Address; Arterial Fatty Streak; Atherosclerosis; Binding; Binding Proteins; Binding Sites; Cell surface; Cells; Data; Development; Extracellular Matrix Degradation; Goals; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Macrophage Colony-Stimulating Factor; Molecular; Neoplasm Metastasis; Pathologic Processes; Pathway interactions; Phenotype; Physiological; Physiological Processes; Plasmin; Plasminogen; Plasminogen Activator; Process; Proteomics; Regulation; Role; Staging; Stimulus; Surface; Testing; Tumor Cell Invasion; Up-Regulation; Wound Healing; base; cell motility; in vivo; insight; macrophage; monocyte; plasminogen receptor; receptor; receptor expression; receptor function; response; tissue processing

DESCRIPTION (provided by applicant): The assembly of plasminogen and plasminogen activators on cell surfaces is a crucial control point for positive regulation of cell surface proteolytic activity necessary in both physiological and pathological processes requiring cell migration. The long-term goal of our laboratory is to understand the mechanisms by which plasminogen binding to cells is regulated, in order to function in physiological and pathological processes. This proposal is based on data demonstrating that up-regulation of plasminogen binding function occurs during differentiation of viable monocytes into viable macrophages. In preliminary studies, we identified three major candidate plasminogen receptors up-regulated in response to M-CSF that have not been recognized previously as plasminogen binding sites on monocytes. The objective of this application is to elucidate the role of M-CSF-up-regulated plasminogen receptors in monocyte/macrophage recruitment. The central hypothesis to be addressed is that plasminogen receptors are up-regulated during monocyte/macrophage maturation and facilitate recruitment of these cells in response to inflammatory stimuli, by promoting plasminogen activation and localizing the proteolytic activity of plasmin on the cell surface. To test this hypothesis we will I) identify the major pro- fibrinolytic plasminogen binding proteins on M-CSF-stimulated cells and quantify their expression during monocyte development in vivo and II) test the hypothesis that M-CSF-up-regulated plasminogen receptors promote plasminogen activation, extracellular matrix degradation and cell migration in vitro and in vivo. We expect that accomplishment of our specific aims will provide fundamental insights that will apply to the regulation of inflammation. Furthermore, because monocyte/macrophage recruitment and infiltration is a key feature of the atherosclerotic lesion, our results should apply to the understanding of atherosclerosis.

描述（由申请人提供）：纤溶酶原和纤溶酶原激活剂在细胞表面的组装是细胞表面蛋白水解活性正调节的关键控制点，该活性在需要细胞迁移的生理和病理过程中是必需的。我们实验室的长期目标是了解纤溶酶原与细胞结合的调节机制，以便在生理和病理过程中发挥作用。该提议基于的数据表明，纤溶酶原结合功能的上调发生在活单核细胞分化为活巨噬细胞的过程中。在初步研究中，我们鉴定了三种主要的候选纤溶酶原受体，它们响应 M-CSF 而上调，这些受体以前未被识别为单核细胞上的纤溶酶原结合位点。本申请的目的是阐明 M-CSF 上调的纤溶酶原受体在单核细胞/巨噬细胞募集中的作用。要解决的中心假设是，纤溶酶原受体在单核细胞/巨噬细胞成熟过程中上调，并通过促进纤溶酶原激活并将纤溶酶的蛋白水解活性定位在细胞表面，促进这些细胞响应炎症刺激而募集。为了检验这一假设，我们将 I) 鉴定 M-CSF 刺激的细胞上主要的纤溶酶原结合蛋白，并量化它们在体内单核细胞发育过程中的表达，II) 检验 M-CSF 上调的纤溶酶原受体促进纤溶酶原激活、细胞外基质降解和细胞体外和体内迁移。我们期望我们特定目标的实现将为炎症的调节提供基本的见解。此外，由于单核细胞/巨噬细胞的募集和浸润是动脉粥样硬化病变的关键特征，因此我们的结果应适用于对动脉粥样硬化的理解。