Gliovascular Mechanisms of Blood-Brain Barrier Disruption in Neuroinflammatory Disease
神经炎症疾病中血脑屏障破坏的胶质血管机制
基本信息
- 批准号:10397055
- 负责人:
- 金额:$ 47.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAnimal ModelAreaAstrocytesAutomobile DrivingAxonBlindnessBloodBlood - brain barrier anatomyBlood PressureBlood VesselsBlood flowCardiovascular DiseasesCell Adhesion MoleculesCell CommunicationCellsCentral Nervous System DiseasesCerebrovascular CirculationCerebrovascular systemChronicClinicClinicalDataDemyelinating DiseasesDemyelinationsDepositionDiseaseEndothelial CellsEndothelinEndothelin ReceptorEndothelin Receptor AntagonistEndothelin-1EndotheliumEventExperimental Autoimmune EncephalomyelitisExtravasationFDA approvedGeneticHistologicHumanHypertensionHypoxiaImageImmuneImmunologicsInfiltrationInflammatoryKnockout MiceLabelLesionLeukocyte TraffickingLeukocytesLinkLocationMediatingMicrogliaMicroscopyModelingMolecularMolecular ProfilingMultiple SclerosisMultiple Sclerosis LesionsMusNeuraxisNeurologic SymptomsNumbnessParalysedPathologyPathway interactionsPatientsPeptidesPeripheralPharmacologyPropertyReceptor InhibitionRegulationRelapseRoleSeverity of illnessSignal TransductionSiteSpinal CordSpinal Cord LesionsStrokeSystemT-LymphocyteTestingTherapeuticTimeTissue BanksTissuesTumor-infiltrating immune cellsValidationVascular Endothelial CellVascular Endotheliumantagonistaxon injurybaseblood-brain barrier disruptionbrain tissuecell typedrug repurposingexperimental studyhuman tissuehypertension treatmentimaging studyin vivoin vivo imaginginhibitormacrophagemigrationmonocytemultiple sclerosis patientmultiple sclerosis treatmentneuroinflammationneuron losspre-clinicalpreventreceptorreceptor expressionrecruittwo-photonvascular abnormality
项目摘要
Abstract
Multiple sclerosis (MS) is a debilitating neuroinflammatory disease of the central nervous system (CNS) with a broad range
of neurological manifestations such as numbness, paralysis, and loss of vision. Disease pathology presents with massive
perivascular lesions where inflammatory demyelination results in axonal damage, the main culprit for the loss of neuronal
function in MS patients. Although a lot is known about cells and molecules involved with disease pathology, what cellular
and molecular mechanisms initiate the immunological cascade against the CNS remain unknown. The earliest signs of
lesions in both human MS patients and in animal models of MS are blood-brain barrier (BBB) disruption and activation of
microglia, which are the resident immune cells of the CNS. Our previous in vivo imaging studies identified microglia as the
earliest responders in experimental autoimmune encephalomyelitis (EAE, an established animal model for MS). We found
that microglia cluster around vessels that leak blood factors into the CNS and thereby determine the perivascular locations
where new lesions form. What causes early vascular alterations, local disruption of blood vessels, and recruitment of
peripheral immune cells that form these perivascular lesions is not known. In this proposal, we will explore the cellular and
molecular mechanisms involved with early vascular alterations and BBB disruption in EAE and MS. We will investigate
whether early perivascular microglial accumulation in EAE involves signaling between microglia and the vessel wall, which
causes such vascular alterations and drives immune cell recruitment to the CNS. Specifically, we will determine whether
activated microglia communicate with the cellular constituents of the cerebral vasculature through the endothelin (ET)
system, which is one of the main molecular mechanisms involved in the regulation of vascular tone, blood pressure, and
blood flow. Besides altering vascular properties, ET-1 also has potent pro-inflammatory effects as it enhances trans-
endothelial passage of monocytes and leukocytes. ET signaling has been implicated in cardiovascular diseases, such as
hypertension and stroke, but little is known about its potential role in MS or its animal models. Our preliminary results and
prior studies suggest that the ET system is a good candidate pathway for inducing reduced cerebral blood flow and vascular
abnormalities in EAE and MS. Our proposed experimental approach combines pharmacological and genetic inhibition
approaches with in vivo imaging of vascular disruption and microglia, macrophages, and T cells in mice undergoing the
course of EAE. Moreover, we will seek to validate our preclinical animal model findings on ET pathway expression across
different types of lesions from MS patients by using the unique human brain tissue bank that we have available at the
Cleveland Clinic. Since ET receptor antagonists are FDA-approved for the treatment of hypertension, our studies have the
potential to provide proof-of-principle validation that repurposing these drugs can be beneficial for the treatment of MS in
human patients.
摘要
多发性硬化(MS)是一种中枢神经系统(CNS)的衰弱性神经炎性疾病,
神经系统的表现,如麻木,瘫痪和视力丧失。疾病病理学表现为大量
炎性脱髓鞘导致轴突损伤的血管周围病变,轴突损伤是神经元损伤的主要原因。
MS患者的功能。尽管我们对与疾病病理学有关的细胞和分子有很多了解,
启动针对CNS的免疫级联反应的分子机制仍然未知。的最早迹象
人MS患者和MS动物模型中的损伤是血脑屏障(BBB)破坏和
小胶质细胞是CNS的常驻免疫细胞。我们以前的体内成像研究确定小胶质细胞是
实验性自身免疫性脑脊髓炎(EAE,一种已建立的MS动物模型)中的最早应答者。我们发现
小胶质细胞聚集在血管周围,这些血管将血液因子泄漏到中枢神经系统中,从而确定血管周围的位置。
形成新的损伤是什么原因导致早期血管改变、局部血管破裂和
形成这些血管周围病变的外周免疫细胞是未知的。在这个建议中,我们将探索细胞和
EAE和MS中早期血管改变和BBB破坏的分子机制。我们将研究
EAE中早期血管周围小胶质细胞积聚是否涉及小胶质细胞和血管壁之间的信号传导,
导致这种血管改变并驱使免疫细胞募集到CNS。具体来说,我们将确定
激活的小胶质细胞通过内皮素(ET)与脑血管的细胞成分进行通讯,
系统,其是参与调节血管张力、血压和血压的主要分子机制之一,
血流除了改变血管特性外,ET-1还具有强有力的促炎作用,因为它增强了反式-
单核细胞和白细胞的内皮通道。ET信号传导与心血管疾病有关,例如
高血压和中风,但很少有人知道它在MS或其动物模型中的潜在作用。我们的初步结果和
先前的研究表明,ET系统是诱导脑血流量减少和血管紧张素转换酶活性降低的良好候选途径。
我们提出的实验方法结合了药理学和遗传抑制
方法,在体内成像的血管破裂和小胶质细胞,巨噬细胞和T细胞在小鼠经历的
EAE的过程此外,我们将寻求验证我们的临床前动物模型中ET通路表达的发现,
不同类型的病变从MS患者通过使用独特的人脑组织库,我们可以在
克利夫兰诊所由于ET受体拮抗剂是FDA批准用于治疗高血压的药物,因此我们的研究表明,
有可能提供原理验证,证明这些药物的再利用有助于治疗MS,
人类病人
项目成果
期刊论文数量(0)
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Dimitrios Davalos其他文献
Dimitrios Davalos的其他文献
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{{ truncateString('Dimitrios Davalos', 18)}}的其他基金
Gliovascular Mechanisms of Blood-Brain Barrier Disruption in Neuroinflammatory Disease
神经炎症疾病中血脑屏障破坏的胶质血管机制
- 批准号:
10153902 - 财政年份:2019
- 资助金额:
$ 47.94万 - 项目类别:
Gliovascular Mechanisms of Blood-Brain Barrier Disruption in Neuroinflammatory Disease
神经炎症疾病中血脑屏障破坏的胶质血管机制
- 批准号:
10615054 - 财政年份:2019
- 资助金额:
$ 47.94万 - 项目类别:
Project 2 Title: The brain brush border and microglial activation in response to ethanol
项目 2 标题:乙醇反应中的脑刷状缘和小胶质细胞激活
- 批准号:
10609541 - 财政年份:2016
- 资助金额:
$ 47.94万 - 项目类别:
Project 2 Title: The brain brush border and microglial activation in response to ethanol
项目 2 标题:乙醇反应中的脑刷状缘和小胶质细胞激活
- 批准号:
10397507 - 财政年份:2016
- 资助金额:
$ 47.94万 - 项目类别:
Project 2 Title: The brain brush border and microglial activation in response to ethanol
项目 2 标题:乙醇反应中的脑刷状缘和小胶质细胞激活
- 批准号:
10056023 - 财政年份:2016
- 资助金额:
$ 47.94万 - 项目类别:
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