Gleevec Protects Neurovascular Unit by Inhibition of PDGFR
格列卫通过抑制 PDGFR 保护神经血管单位
基本信息
- 批准号:8993927
- 负责人:
- 金额:$ 19.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAffectAntineoplastic AgentsAstrocytesBehavioralBlood - brain barrier anatomyBlood VesselsBrainBrain EdemaBrain InjuriesBrain hemorrhageCapillary Endothelial CellCerebral EdemaCerebral hemisphere hemorrhageCerebrovascular SpasmCerebrumClinicalDataEndothelial CellsEndotheliumEvaluationExtravasationFDA approvedFoundationsFutureGap JunctionsGleevecGoalsHematomaIn VitroIndividualInjuryIntercellular JunctionsInvestigationIschemic Brain InjuryLIM Domain Kinase 1LeftMAP Kinase GeneMAPK1 geneMAPK14 geneMAPKAPK2 geneMagnetic Resonance ImagingMediatingModelingMorbidity - disease rateMusNatureNeurologicNeurological outcomeNeuronsOutcomePathologyPathway interactionsPatientsPericytesPhenotypePhosphorylationPlatelet-Derived Growth FactorPlatelet-Derived Growth Factor ReceptorPlayProteinsPublishingReceptor Protein-Tyrosine KinasesReceptor SignalingReportingResearchRoleSignal PathwaySmooth MuscleSmooth Muscle MyocytesStressStress FibersStrokeSubarachnoid HemorrhageTestingTraumatic Brain InjuryUnited StatesVascular Smooth Muscleactin depolymerizing factorcell typecerebral arterycofilindisabilityeffective therapyimprovedinhibitor/antagonistmembermortalitymouse modelneurovascularneurovascular injuryneurovascular unitnoveloutcome forecastpreventprotective effectresearch clinical testingtherapeutic targettreatment strategyvasogenic edema
项目摘要
At present, there is no effective treatment for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Secondary brain injury after ICH is known to involve brain edema, disruption ofthe blood brain barrier (BBB), and neurological deficits. Platelet derived growth factor receptors (PDGFRs) are a subfamily of tyrosine kinase receptors including two members, PDGFR-a and PDGFR-p. PDGFRs are expressed in various cell-types in the brain and participate in smooth muscle phenotype changes. Our previous study has found that PDGFR suppression by Gleevec, a PDGFR inhibitor, reduces brain edema and BBB leakage in a mouse model of ICH. Others also reported that PDGFR is associated with BBB disruption in ischemic brain injury. However the mechanisms of PDGFR-associated BBB damage remain unclear and the role of smooth muscle phenotype changes in ICH injury has never been studied. Our preliminary data showed that Gleevec-induced BBB protection after ICH is associated with inhibition of p38 MAPK pathway. Our preliminary study also made a groundbreaking discovery that ICH results the loss of myogenic tone and the changes of smooth muscle phenotype proteins in the cerebral arteries near the hematoma; Gleevec treatment antagonizes these changes. Therefore, we hypothesize that PDGFR-suppression with Gleevec will reduce BBB disruption via protecting intercellular junctions and preventing smooth muscle phenotype changes thus improving neurological outcome after ICH. Gleevec treatment will also prevent neurovascular damage in other types of hemorrhagic brain injury including subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI). The following studies are proposed to test our hypothesis: Aim 1 will determine the neurovascular protective effect of Gleevec administration after ICH, including BBB integrity, smooth muscle phenotype changes and long-term neurological outcomes. Aim 2 will investigate the role of PDGFR-p38- MAPK-MAPKAPK2-LIMK1 pathway in ICH-induced BBB disruption. Aim 3 will determine the neurovascular protective effect of Gleevec treatment in SAH and TBI models. Our long-term goal is to explore the importance of PDGFR involved in neurovascular injury for future evaluation as a potential therapeutic target against hemorrhagic brain injury in patients
脑出血是一种常见且常常致命的脑卒中亚型,目前尚无有效的治疗方法。脑出血后继发性脑损伤包括脑水肿、血脑屏障(BBB)破坏和神经功能缺损。血小板衍生生长因子受体(pdgfr)是酪氨酸激酶受体的一个亚家族,包括两个成员,PDGFR-a和PDGFR-p。PDGFRs在大脑的各种细胞类型中表达,并参与平滑肌表型的改变。我们之前的研究发现,PDGFR抑制剂格列卫抑制PDGFR,可以减少脑出血小鼠模型的脑水肿和血脑屏障渗漏。其他人也报道PDGFR与缺血性脑损伤中的血脑屏障破坏有关。然而,pdgfr相关血脑屏障损伤的机制尚不清楚,平滑肌表型改变在脑出血损伤中的作用从未被研究过。我们的初步数据显示,格列卫诱导的脑出血后血脑屏障保护与p38 MAPK通路的抑制有关。我们的初步研究也取得了突破性的发现,ICH导致血肿附近脑动脉肌原性张力的丧失和平滑肌表型蛋白的改变;格列卫治疗可以对抗这些变化。因此,我们假设格列卫抑制pdgfr将通过保护细胞间连接和防止平滑肌表型改变来减少血脑屏障破坏,从而改善脑出血后的神经预后。格列卫治疗还可以预防其他类型出血性脑损伤的神经血管损伤,包括蛛网膜下腔出血(SAH)和创伤性脑损伤(TBI)。我们提出以下研究来验证我们的假设:目的1将确定脑出血后给予格列卫的神经血管保护作用,包括血脑屏障完整性、平滑肌表型改变和长期神经预后。目的2将研究PDGFR-p38- MAPK-MAPKAPK2-LIMK1通路在ich诱导的血脑屏障破坏中的作用。目的3将确定格列卫治疗在SAH和TBI模型中的神经血管保护作用。我们的长期目标是探索PDGFR参与神经血管损伤的重要性,以便将来评估其作为出血性脑损伤患者的潜在治疗靶点
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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Jiping Tang其他文献
Jiping Tang的其他文献
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{{ truncateString('Jiping Tang', 18)}}的其他基金
Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage
利用生发基质出血后的血凝块清除机制
- 批准号:
10528489 - 财政年份:2021
- 资助金额:
$ 19.46万 - 项目类别:
Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage
利用生发基质出血后的血凝块清除机制
- 批准号:
10331887 - 财政年份:2021
- 资助金额:
$ 19.46万 - 项目类别:
Harnessing blood clot clearance mechanisms after germinal matrix hemorrhage
利用生发基质出血后的血凝块清除机制
- 批准号:
10203222 - 财政年份:2021
- 资助金额:
$ 19.46万 - 项目类别:
Investigating the role of mast cells in neonatal germinal matrix hemorrhage
研究肥大细胞在新生儿生发基质出血中的作用
- 批准号:
9452501 - 财政年份:2017
- 资助金额:
$ 19.46万 - 项目类别:
Role of NADPH Oxidase in ICH-Induced Brain Injury
NADPH 氧化酶在 ICH 引起的脑损伤中的作用
- 批准号:
6958794 - 财政年份:2005
- 资助金额:
$ 19.46万 - 项目类别:
Role of NADPH Oxidase in ICH-Induced Brain Injury
NADPH 氧化酶在 ICH 引起的脑损伤中的作用
- 批准号:
7140282 - 财政年份:2005
- 资助金额:
$ 19.46万 - 项目类别:
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