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
脑动静脉畸形(BAVM)病灶内的血管具有异常的管壁结构和
容易破裂,导致危及生命的颅内出血和长期残疾。脑区
动静脉动静脉畸形破裂通常是不可预测的。目前还没有预防这种疾病的特效药。
血管内皮细胞生长因子异常高水平与脑动静脉畸形有关
病理生理学。研究表明,阻断血管内皮生长因子信号可阻止bAVM的进展。反-
血管内皮生长因子抗体和酪氨酸激酶抑制剂(TKIs)已被用来阻断血管内皮细胞生长因子信号转导
很多场景。然而,抗体和TKI都会对患者产生不良影响。由于bAVM
是慢性和活动性的血管新生病变,需要长期的血管内皮生长因子抑制来抑制bAVM
进展和稳定动静脉畸形血管。抗体和TKI需要重复剂量,这是昂贵的
而且很不方便。此外,最近的研究表明,TKI对小鼠皮肤Avm没有影响,并且
血管生成信号转导的血管内皮生长因子受体-2(VEGFR-2)的基因缺失可防止
过度的血管生成,但不能完全逆转AVM的形成。这些数据表明,阻止
血管内皮生长因子的血管生成作用不足以治疗某些组织中的AVM。需要一种更好的试剂来
预防脑动静脉畸形的发展和破裂。
含有VEGFR-1胞外区的可溶性FMS相关酪氨酸激酶1结合
血管内皮生长因子具有高亲和力,从而通过其膜结合受体减少血管内皮生长因子的信号转导。
更重要的是,sFlt1在维持周细胞正常功能方面起着直接作用。我们已经测试了一个
SFlt1基因治疗策略在我们的bAVM小鼠模型中,并已表明静脉注射
表达sFlt1的腺相关病毒载体可降低bAVM的严重程度。然而,无处不在的
SFlt1的表达引起了一些不良反应。在这项研究中,我们希望证明sFlt1
通过抑制血管内皮生长因子信号转导和改善周细胞对血管的黏附来改善bAVM血管完整性
内皮细胞(目标1)。我们还将测试靶向sFlt1表达是否会降低bAVM的严重性
使用AAV载体以最小的副作用感染神经元或内皮细胞
与神经元特异性启动子或脑内皮细胞特异性启动子(Aim 2)结合,以及
减少小胶质细胞/巨噬细胞的浸润可提高sFlt1的治疗效果(目标3)。我们还将
研究sFlt1在所有目标中产生治疗效果的机制。的首要目标是
本课题旨在探索一种安全有效的预防脑动静脉畸形出血的方法。
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
-
批准号:10554394
-
项目类别:
-
资助金额:$57.4万
-
财政年份:2020
-
负责人:HUA SU
-
依托单位:
Reduction of Brain AVM Severity through Inhibition of Pathogenic Angiogenesis
-
批准号:10329960
-
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
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依托单位:
Cell type-specific influences on HHT pathogenesis
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批准号:8816957
-
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
-
批准号:9407153
-
项目类别:
-
资助金额:$39.1万
-
财政年份:2015
-
负责人:HUA SU
-
依托单位:
Cell type-specific influences on HHT pathogenesis
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批准号:8995684
-
项目类别:
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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
-
批准号:8702392
-
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
-
依托单位:
Soluble VEGF receptor therapy for brain arteriovenous malformation
-
批准号:8833344
-
项目类别:
-
资助金额:$39.59万
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财政年份:2014
-
负责人:HUA SU
-
依托单位:
Targeted Gene Expression in Ischemic Brain by Intravenous Delivery
-
批准号:7876141
-
项目类别:
-
资助金额:$19.31万
-
财政年份:2010
-
负责人:HUA SU
-
依托单位:
Targeted Gene Expression in Ischemic Brain by Intravenous Delivery
-
批准号:8018592
-
项目类别:
-
资助金额:$18.93万
-
财政年份:2010
-
负责人:HUA SU
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依托单位:
Laboratory
-
批准号:8376492
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项目类别:
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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:
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资助金额:$23.59万
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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:8243602
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项目类别:
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资助金额:$21.43万
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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:8451443
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项目类别:
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资助金额:$18.68万
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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:7663704
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项目类别:
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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
-
批准号:8629502
-
项目类别:
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资助金额:$31.11万
-
财政年份:1990
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负责人:HUA SU
-
依托单位:
Uncover the Pathogenesis of Brain Arteriovenous Malformation
-
批准号:10568988
-
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
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批准号:10308029
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项目类别:
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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
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依托单位:
Hemodynamics of Cerebral Arteriovenous Malformations
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批准号:8786112
-
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:
Hemodynamics of Cerebral Arteriovenous Malformations
-
批准号:8415938
-
项目类别:
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资助金额:$31.96万
-
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:10084324
-
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