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:
- 金额:$ 31.38万
- 依托单位:
- 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:
- 关键词:AcuteAdultAnticoagulantsBlocking AntibodiesBlood VesselsBlood coagulationBrainCCM1 geneChronicCytoprotectionDepositionDevelopmentDiseaseDisease ProgressionEndothelial CellsEndotheliumF2R geneFactor V Leiden mutationHemophilia AHemorrhageHemosiderinHumanHypoxiaHypoxia Inducible FactorImpairmentIntercellular JunctionsInterventionLesionMSH2 geneModelingMonoclonal AntibodiesMorbidity - disease rateMusPathogenesisPathway interactionsPerinatalPreclinical TestingProtein CResearchResistanceRoleSepsisSignal TransductionSourceStrokeSymptomsTestingThrombomodulinactivated Protein Cactivated protein C receptorcerebral cavernous malformationsfactor V Leidengene functioninsightloss of functionmortalitymutantneonatal miceneurovascularnew therapeutic targetpharmacologicpreventtherapeutic 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mark HOWARD Ginsberg其他文献
Mark HOWARD Ginsberg的其他文献
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{{ truncateString('Mark HOWARD Ginsberg', 18)}}的其他基金
Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis
炎症、止血和血栓形成的细胞机制
- 批准号:
10229365 - 财政年份:2020
- 资助金额:
$ 31.38万 - 项目类别:
Direct Rap1-talin interaction in platelets, leukocytes, and endothelial cells
Rap1-talin 在血小板、白细胞和内皮细胞中的直接相互作用
- 批准号:
10229368 - 财政年份:2020
- 资助金额:
$ 31.38万 - 项目类别:
Cellular Mechanisms of Inflammation, Hemostasis, and Thrombosis
炎症、止血和血栓形成的细胞机制
- 批准号:
10676869 - 财政年份:2020
- 资助金额:
$ 31.38万 - 项目类别:
Direct Rap1-talin interaction in platelets, leukocytes, and endothelial cells
Rap1-talin 在血小板、白细胞和内皮细胞中的直接相互作用
- 批准号:
10676892 - 财政年份:2020
- 资助金额:
$ 31.38万 - 项目类别:
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
- 批准号:
10417155 - 财政年份:2015
- 资助金额:
$ 31.38万 - 项目类别:
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
- 批准号:
10220146 - 财政年份:2015
- 资助金额:
$ 31.38万 - 项目类别:
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