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Proteins of Coagulation Pathways

凝血途径的蛋白质

基本信息

批准号：
7748029
负责人：
JOHN H GRIFFIN
金额：
$ 56.86万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7748029
关键词：
3-Dimensional Affect Anticoagulants Arteries Basic Science Binding Binding Proteins Binding Sites Biological Assay Biological Markers Blood Blood Clot Blood Coagulation Factor Blood coagulation Carnitine Chimera organism Clinical Clinical Research Coagulation Process Complex Data Diagnosis Disease Dyslipidemias Elements Energy Transfer Factor Va Factor X Factor Xa Fatty acid glycerol esters Freezing Functional disorder Funding Generations Glucosylceramides Goals Hand Knowledge Label Leg Life Link Lipid Binding Lipids Lung Maps Membrane Methods Minor Molecular Mutation Myocardial Infarction Pathway interactions Patients Phospholipid Transfer Proteins Phospholipids Plasma Plasma Proteins Property Protein Binding Proteins Prothrombin Recombinants Registries Regulation Risk Sampling Serum amyloid A protein Solutions Sphingosine Study Subject Surface Surface Plasmon Resonance Testing Thrombin Thrombophilia Thromboplastin Thrombosis Translating Translational Research Variant Veins Venous Venous Thrombosis base bench to bedside clinically relevant improved innovation insight lipid transfer protein mutant novel plasma phospholipid transfer protein prothrombinase complex

项目摘要

This revised renewal two year ARRA-funded project extends the PI's basic and clinical research on regulation of blood coagulation and on translational clinical research of venous thrombosis. Thrombosis is strongly linked to an imbalance of anticoagulant and procoagulant mechanisms. Three of four specific aims involve basic studies of novel plasma molecules that regulate clotting while the last aim involves translational research to identify novel biomarkers for thrombosis. For aims 1 and 2, we hypothesize that thrombin generation can be influenced by minor abundance single chain plasma lipids, so-called "soluble" lipids. Based on Surface Plasmon Resonance (SPR) binding studies and on clotting assays, we hypothesize that anticoagulant acyl carnitines, including palmitoyl carnitine, directly inhibit coagulation factor Xa by binding to Xa. In preliminary studies, palmitoyl carnitine binds to Gla-domainless-factor Xa and inhibits its activity. These preliminary data and the proposed experimentation thus relate to a novel paradigm for the effects of plasma lipids on coagulation pathways. Recombinant factor X/IX chimeras and variant factor X molecules from various species will be used to identify putative lipid binding domains on factor Xa. For aim 2, we hypothesize that plasma phospholipid transfer protein (PLTP) can directly influence plasma coagulability and thrombin generation by novel direct interactions with clotting factors. SPR preliminary data show that PLTP binds to specific clotting factors. For aim 3, we will determine some of the three dimensional structural properties of the prothrombinase complex comprising factors Xa, Va and prothrombin on phospholipid membranes. First, we will introduce Cys mutations and prepare fluorescently labeled factor Va. Then we will use Forster Resonance Energy Transfer (FRET) to generate a set of multiple point- to-point and point-to-plane distances that can be used to generate and then interpret FRET-derived distances for the prothrombinase complex. For aim 4, based on the hypothesis that imbalances of plasma anticoagulant minor abundance lipids are linked to thrombosis risk, we will use already available frozen plasma samples from thrombosis patients and matched controls to determine if certain targeted plasma lipids or two lipid binding plasma proteins (PLTP or serum amyloid A) are biomarkers for thrombosis. This project will increase insights into the pathophysiology of thrombosis and may improve diagnosis and treatment of thrombosis.

这个修订后的续期两年arra资助的项目扩展了PI的基础和临床