Reduction of Brain AVM Severity through Inhibition of Pathogenic Angiogenesis
Reduction of Brain AVM Severity through Inhibition of Pathogenic Angiogenesis
批准号:
10083769
负责人:
HUA SU
金额:
$57.4万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-01 至 2025-01-31
关键词:
AdhesionsAdverse effectsAffinityAngiogenic FactorAntibodiesArteriovenous malformationAttenuatedBindingBloodBlood - brain barrier anatomyBrainBrain hemorrhageCellsChronicCytomegalovirusDataDevelopmentDoseEndothelial CellsEndotheliumEngineeringExploratory/Developmental Grant for Diagnostic Cancer ImagingExtracellular DomainExtravasationFLT1 geneFunctional disorderGene ProteinsGenesGeneticGoalsGrowthGrowth Factor InhibitionHemorrhageHumanInfiltrationInflammationInflammatoryInjectionsInterruptionIntestinesIntracranial HemorrhagesIntravenousIschemic StrokeKDR geneKidney GlomerulusLesionLifeMedicalMembraneMethodsMicrogliaMinorMusNatural HistoryNeuronsOrganPathogenesisPathogenicityPathologic NeovascularizationPatientsPericytesPhenotypePlayProcessProtein Tyrosine KinaseProteinsRattusReagentRoleRuptureSeveritiesSignal TransductionSkinStructureSymptomsSynapsinsSystemTestingTetanus Helper PeptideTherapeutic EffectTight JunctionsTissuesToxic effectTreatment-related toxicityTubeTyrosine Kinase InhibitorVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth Factorsadeno-associated viral vectorangiogenesisautocrineblood-brain barrier permeabilizationbrain arteriovenous malformationscell typecostcytokinedisabilityefficacy evaluationexperimental studyextracellularfeasibility testinggene therapyimprovedliver inflammationmacrophagemouse modelnovel therapeutic interventionoverexpressionpodocytepreventpromoterreceptor bindingside effectsingle-cell RNA sequencingvector
中文摘要
摘要
英文摘要
Abstract
Vessels in the nidus of brain arteriovenous malformation (bAVM) have abnormal wall structure and
are prone to rupture, causing life-threatening intracranial hemorrhage and long-term disability. Brain
AVM rupture is often unpredictable. There is no specific therapy for preventing it.
An abnormally high level of vascular endothelial growth factor (VEGF) has been implicated in bAVM
pathophysiology. Studies show that interruption of VEGF signaling prevents bAVM progression. Anti-
VEGF antibodies and tyrosine kinase inhibitors (TKIs) have been used to block VEGF signaling in
many settings. However, both antibodies and TKIs cause adverse effects in patients. Since bAVMs
are chronic and active angiogenic lesions, long-term VEGF inhibition will be needed to inhibit bAVM
progression and stabilize AVM vessels. Antibodies and TKIs need repeated dosing, which is costly
and inconvenient. In addition, recent studies show that TKIs have no effect on mouse skin AVMs, and
genetic deletion of the angiogenic signal-transducing VEGF receptor-2 (VEGFR-2) prevents
excessive angiogenesis but does not fully revert AVM formation. These data suggest that blocking
VEGF angiogenic effect is insufficient to treat AVM in certain tissues. A better reagent is needed to
prevent bAVM development and rupture.
Soluble FMS-related tyrosine kinase 1 (sFLT1) containing extracellular domain of VEGFR-1 binds
VEGF with high affinity, and thus reduces VEGF signaling through its membrane-bound receptors.
More importantly, sFLT1 has a direct role in maintaining normal pericyte function. We have tested a
sFLT1 gene therapy strategy in our bAVM mouse models, and have shown that intravenous delivery
of an adeno-associated viral vector expressing sFLT1 reduces bAVM severity. However, ubiquitous
expression of sFLT1 caused some adverse effects. In this study, we hope to demonstrate that sFLT1
improves bAVM vessel-integrity by inhibiting VEGF signaling and improving adhesion of pericytes to
endothelial cells (Aim 1). We will also test whether targeted sFLT1 expression reduces bAVM severity
with minimal side effects using AAV vectors that infect neurons or endothelial cells specifically in
combination with neuron specific or brain endothelial specific promoter (Aim 2), and whether
reduction of microglia/macrophage infiltration enhances sFLT1 therapeutic effect (Aim 3). We will also
investigate mechanisms by which sFLT1 therapeutic effects occur in all aims. The overarching goal of
this project is to develop a safe and effective method to prevent bAVM hemorrhage.
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会议论文
Reduction of Brain AVM Severity through Inhibition of Pathogenic Angiogenesis
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批准号:10554394
-
项目类别:
-
资助金额:$57.4万
-
财政年份:2020
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负责人:HUA SU
-
依托单位:
Reduction of Brain AVM Severity through Inhibition of Pathogenic Angiogenesis
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批准号:10329960
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项目类别:
-
资助金额:$57.4万
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财政年份:2020
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负责人:HUA SU
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依托单位:
Cell type-specific influences on HHT pathogenesis
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批准号:8816957
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项目类别:
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资助金额:$39.64万
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财政年份:2015
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负责人:HUA SU
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依托单位:
Cell type-specific influences on HHT pathogenesis
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批准号:9407153
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项目类别:
-
资助金额:$39.1万
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财政年份:2015
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负责人:HUA SU
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依托单位:
Cell type-specific influences on HHT pathogenesis
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批准号:8995684
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项目类别:
-
资助金额:$39.7万
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财政年份:2015
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负责人:HUA SU
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依托单位:
Soluble VEGF receptor therapy for brain arteriovenous malformation
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批准号:8702392
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项目类别:
-
资助金额:$39.44万
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财政年份:2014
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负责人:HUA SU
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依托单位:
Soluble VEGF receptor therapy for brain arteriovenous malformation
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批准号:8833344
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项目类别:
-
资助金额:$39.59万
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财政年份:2014
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负责人:HUA SU
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依托单位:
Targeted Gene Expression in Ischemic Brain by Intravenous Delivery
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批准号:7876141
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项目类别:
-
资助金额:$19.31万
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财政年份:2010
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负责人:HUA SU
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依托单位:
Targeted Gene Expression in Ischemic Brain by Intravenous Delivery
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批准号:8018592
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项目类别:
-
资助金额:$18.93万
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财政年份:2010
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负责人:HUA SU
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依托单位:
Laboratory
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批准号:8376492
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项目类别:
-
资助金额:$22.74万
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财政年份:2003
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负责人:HUA SU
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依托单位:
Laboratory
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批准号:8049030
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项目类别:
-
资助金额:$23.59万
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财政年份:2003
-
负责人:HUA SU
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依托单位:
Laboratory
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批准号:8243602
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项目类别:
-
资助金额:$21.43万
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财政年份:2003
-
负责人:HUA SU
-
依托单位:
Laboratory
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批准号:8451443
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项目类别:
-
资助金额:$18.68万
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财政年份:2003
-
负责人:HUA SU
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依托单位:
Laboratory
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批准号:7663704
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项目类别:
-
资助金额:$24.63万
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财政年份:2003
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负责人:HUA SU
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依托单位:
Hemodynamics of Cerebral Arteriovenous Malformations
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批准号:8629502
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项目类别:
-
资助金额:$31.11万
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财政年份:1990
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负责人:HUA SU
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依托单位:
Uncover the Pathogenesis of Brain Arteriovenous Malformation
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批准号:10568988
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项目类别:
-
资助金额:$50.48万
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财政年份:1990
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负责人:HUA SU
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依托单位:
Uncover the Pathogenesis of Brain Arteriovenous Malformation
-
批准号:10308029
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项目类别:
-
资助金额:$52.35万
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财政年份:1990
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负责人:HUA SU
-
依托单位:
Hemodynamics of Cerebral Arteriovenous Malformations
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批准号:8415938
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项目类别:
-
资助金额:$31.96万
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财政年份:1990
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负责人:HUA SU
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依托单位:
Hemodynamics of Cerebral Arteriovenous Malformations
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批准号:8786112
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项目类别:
-
资助金额:$31.26万
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财政年份:1990
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负责人:HUA SU
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依托单位:
Uncover the Pathogenesis of Brain Arteriovenous Malformation
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批准号:10084324
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项目类别:
-
资助金额:$53.74万
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财政年份:1990
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负责人:HUA SU
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依托单位:
海外基金