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Anti-Coagulant and Cytoprotective activity in CCM pathogenesis

CCM 发病机制中的抗凝血和细胞保护活性

基本信息

批准号：
10621253
负责人：
Mark HOWARD Ginsberg
金额：
$ 31.38万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621253
关键词：
Acute Adult Anticoagulants Blocking Antibodies Blood Vessels Blood coagulation Brain CCM1 gene Chronic Cytoprotection Deposition Development Disease Disease Progression Endothelial Cells Endothelium F2R gene Factor V Leiden mutation Hemophilia A Hemorrhage Hemosiderin Human Hypoxia Hypoxia Inducible Factor Impairment Intercellular Junctions Intervention Lesion MSH2 gene Modeling Monoclonal Antibodies Morbidity - disease rate Mus Pathogenesis Pathway interactions Perinatal Preclinical Testing Protein C Research Resistance Role Sepsis Signal Transduction Source Stroke Symptoms Testing Thrombomodulin activated Protein C activated protein C receptor cerebral cavernous malformations factor V Leiden gene function insight loss of function mortality mutant neonatal mice neurovascular new therapeutic target pharmacologic prevent therapeutic target

项目摘要

ABSTRACT Cerebral Cavernous Malformations (CCM) are subject to acute and chronic bleeding that is a major source of morbidity and mortality in this disease. We have found that endothelial cells within murine and human CCM express markedly increased levels of thrombomodulin (TM) and endothelial protein C receptor (EPCR), which lead to activation of endogenous anti-coagulant protein C. We hypothesize that CCM form an anti-coagulant vascular domain and that activated Protein C (APC) contributes to bleeding in CCM. APC can also exert a cytoprotective effect on endothelium by signaling via PAR1 resulting in, among other effects, stabilization of endothelial cell-cell junctions. Indeed, this cytoprotective effect of APC has been exploited by creation of APC loss of function mutants that selectively maintain cytoprotective activity. We thus hypothesize that APC cytoprotective activity may limit morbidity from CCM as it does in experimental stroke. To genetically test this hypothesis, we will examine the bleeding in the acute murine CCM models in Factor V Leiden (F5R504Q/wt) mice, which are resistant to the anti-coagulant effect of APC. As a second approach we will test the effect of MAPC1591, a monoclonal antibody that blocks the anti-coagulant activity of APC in acute models of CCM. To test the effects of cytoprotective activity, we will examine acute CCM lesion development and bleeding in F2rR46Q/R46Q mice bearing PAR1 that is selectively resistant to APC cleavage. Conversely, we will examine the effect of 3K3A-APC, a loss of function APC mutant that is selectively impaired in anti-coagulant function in acute and chronic CCM models. We will exploit our observation that a brief period of hypoxia or pharmacological stabilization of Hypoxia-inducible factor 1A markedly exacerbates acute CCM formation in perinatal mice and enables a robust subacute model that manifests in adult mice. This subacute model which manifests both bleeding and hemosiderin deposition, will be used to test the interventions described in aims 1 and 2. Completion of these Aims will provide mechanistic insight into the role of the marked increase of TM and EPCR that is observed in CCM and provide important preclinical tests of the idea that hemorrhage or disease progression can be influenced by manipulating pathways that are already being therapeutically targeted in diseases such as stroke, sepsis, and hemophilia.

摘要