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Identifying Thrombosis Modifier Genes and Novel Anticoagulants in Zebrafish

鉴定斑马鱼中的血栓调节基因和新型抗凝剂

基本信息

批准号：
8150065
负责人：
David Ginsburg
金额：
$ 23万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8150065
关键词：
Anticoagulants Antithrombin III Biological Models Blood Vessels Blood specimen Candidate Disease Gene Cell physiology Cerebral hemisphere hemorrhage Chemicals Clinical Complex Defect Disease Endothelial Cells Engineering Enhancers Equilibrium Fishes Gene Expression Gene Mutation Genes Genetic Genetic Models Genome Genomics Hemophilia A Hemorrhage Hemorrhagic Disorders Hemostatic Agents Hemostatic function Human In Vitro Induced Mutation Lead Libraries Modeling Morbidity - disease rate Mus Mutagenesis Mutation Orthologous Gene Pathologic Patients Pharmacologic Substance Phenotype Predisposition Protein C Protein C Deficiency Proteins Reagent Regulation Regulator Genes Screening procedure Severities Severity of illness Streptococcus pyogenes Streptokinase Suppressor Genes System Testing Therapeutic Thrombophilia Thrombosis Warfarin Zebrafish Zebrafish Proteins base citrate carrier factor V Leiden high throughput screening in vivo insight mortality mutant novel novel strategies small molecule libraries tool von Willebrand Disease

项目摘要

Identifying Thrombosis Modifier Genes and Novel Anticoagulants in Zebrafish This project will take advantage of the powerful genetic tools available in zebrafish to conduct a large scale genomic screen for hemostasis regulatory genes that could modify the severity of human hemorrhagic and thrombotic disorders. This system will also facilitate a novel approach for high-throughput screening of chemical compound libraries in an effort to identify new candidate anticoagulant and hemostatic therapeutics. In preliminary studies, we have positionally cloned a novel ENU-induced mutation in the zebrafish pak2a gene that results in intracerebral hemorrhage, likely due to a defect in endothelial cell function and vascular integrity. We have also engineered a specific mutation (M385L) associated with human protein C deficiency into the zebrafish protein C gene. Additional preliminary studies include a high throughput chemical screen that successfully identified compounds that modulate streptokinase gene expression in pathogenic group A streptococci. In Specific Aim I we will characterize M385L and additional engineered zebrafish protein C mutants to develop in vivo thrombosis models that can be used as the basis for both positive and negative genetic and pharmacologic screens. Specific Aim II will perform large scale chemical library screens to identify "enhancer" compounds that induce thrombosis in partially protein C deficient fish and "suppressor" compounds that "rescue" a lethal thrombosis model. Aim III will use the same zebrafish models to perform whole genome END mutagenesis screens to identify both prothrombotic and anticoagulant modifier genes. Taken together, these studies should identify multiple candidate genes for modifiers of human hemorrhagic and thrombotic disorders, provide new insight into the regulation of hemostasis in vivo, and suggest novel pharmaceutical agents for the treatment of bleeding and thrombosis in humans.

斑马鱼血栓形成修饰基因和新型抗凝血剂的鉴定