权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of plasminogen-dependent cell functions by the novel receptor, Plg-RKT

新型受体 Plg-RKT 调节纤溶酶原依赖性细胞功能

基本信息

批准号：
8913335
负责人：
Lindsey A Miles
金额：
$ 9.99万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-06 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913335
关键词：
Address Binding Binding Proteins Biological Assay C-terminal Carboxypeptidase B Cardiovascular Diseases Cell physiology Cell surface Cells Chemotaxis Defect Development Disease Eukaryotic Cell Exhibits Extracellular Matrix Goals In Vitro Inflammation Inflammatory Inflammatory Response Integral Membrane Protein Knockout Mice Knowledge Laboratories Lysine Mediating Metastatic Neoplasm to the Bone Molecular Mus Neoplasm Metastasis Neurites Neurosecretory Systems Orthologous Gene Pathologic Processes Peptide antibodies Phase Phenotype Physiological Processes Plasmin Plasminogen Plasminogen Activator Process Proteins Public Health Reaction Regulation Reporting Research Solutions Structure Testing Tissues Tumor Cell Invasion Urokinase Plasminogen Activator Receptor Wound Healing base cell motility domain mapping in vivo inhibitor/antagonist insight macrophage matrigel migration mimetics monocyte mouse model myogenesis novel plasminogen receptor prohormone receptor screening small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): Localization of plasminogen on cell surfaces is a crucial control point for positive regulation of cell surface plasmin proteolytic activity that facilitates both physiological and pathological processes requiring cell migration. The long-term goal of our laboratory is to understand mechanisms by which plasminogen receptors regulate pathological and physiological processes. This proposal is based on our discovery of a new protein, the plasminogen receptor, Plg-RKT that has a unique structure: Plg-RKT is an integral membrane protein that exposes a C-terminal lysine on the cell surface, in an orientation to bind plasminogen. Plg-RKT functions as a developmentally regulated plasminogen receptor that promotes plasminogen activation on monocytes and regulates invasion of monocytes through extracellular matrices. Plg-RKT is necessary for optimal plasminogen- dependent macrophage recruitment in the inflammatory response in vivo. In other novel results, Plg-RKT is highly co-localized with the receptor for the major plasminogen activator synthesized by macrophages, the urokinase plasminogen activator receptor (uPAR) and physically associates with uPAR. The objective of this application is to elucidate the molecular mechanisms by which Plg-RKT regulates plasminogen-dependent macrophage recruitment in the inflammatory response. The central hypothesis to be addressed is that Plg-RKT regulates plasminogen-dependent macrophage recruitment by promoting plasminogen activation, extracellular matrix invasion and chemotaxis. To address our hypothesis, our specific aims are: 1) to test the hypothesis that Plg-RKT regulates specific uPAR-dependent functions and that uPAR regulates specific Plg-RKT-dependent functions in plasminogen activation and cell migration; 2) to identify molecular determinants of the physical association of Plg-RKT with uPAR; 3) To identify mechanisms by which Plg-RKT regulates functions of plasminogen in vivo. Studies will be performed in cell based assays and in vivo using novel function blocking anti- Plg-RKT antibodies, peptide mimetics and a new Plg-RKT knockout mouse model. We expect that accomplishment of our specific aims will provide fundamental insights that should apply to understanding mechanisms of regulation of inflammation as well as regulation of other physiological and pathological processes dependent on cell migration.

描述（由申请方提供）：纤溶酶原在细胞表面的定位是细胞表面纤溶酶蛋白水解活性正调控的关键控制点，有助于需要细胞迁移的生理和病理过程。我们实验室的长期目标是了解纤溶酶原受体调节病理和生理过程的机制。该提议是基于我们发现了一种新的蛋白质，纤溶酶原受体，Plg-RKT，其具有独特的结构：Plg-RKT是一种整合的膜蛋白，其暴露细胞表面上的C-末端赖氨酸，以结合纤溶酶原的方向。Plg-RKT作为发育调节的纤溶酶原受体发挥作用，其促进单核细胞上的纤溶酶原活化并调节单核细胞通过细胞外基质的侵袭。Plg-RKT是体内炎症反应中最佳纤溶酶原依赖性巨噬细胞募集所必需的。在其他新的结果中，Plg-RKT与巨噬细胞合成的主要纤溶酶原激活物的受体尿激酶纤溶酶原激活物受体（uPAR）高度共定位，并与uPAR物理缔合。本申请的目的是阐明Plg-RKT调节炎症反应中纤溶酶原依赖性巨噬细胞募集的分子机制。要解决的中心假设是Plg-RKT通过促进纤溶酶原激活、细胞外基质侵袭和趋化性来调节纤溶酶原依赖性巨噬细胞募集。为了解决我们的假设，我们的具体目标是：1）检验Plg-RKT调节特异性uPAR依赖性功能和uPAR调节纤溶酶原激活和细胞迁移中特异性Plg-RKT依赖性功能的假设; 2）鉴定Plg-RKT与uPAR物理结合的分子决定因素; 3）鉴定Plg-RKT调节体内纤溶酶原功能的机制。研究将在基于细胞的测定中进行，并使用新的功能阻断抗Plg-RKT抗体、肽模拟物和新的Plg-RKT敲除小鼠模型在体内进行。我们期望，我们的具体目标的实现将提供基本的见解，应适用于了解炎症的调节机制，以及其他生理和病理过程的调节依赖于细胞迁移。