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:10615054
- 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 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAnimal ModelAreaAstrocytesAutomobile DrivingBlindnessBloodBlood - brain barrier anatomyBlood PressureBlood VesselsBlood flowCardiovascular DiseasesCell Adhesion MoleculesCell CommunicationCellsCentral Nervous SystemCentral Nervous System DiseasesCerebrovascular CirculationCerebrovascular systemChronicClinicClinicalCommunicationDataDemyelinating DiseasesDemyelinationsDepositionDiseaseDisease remissionEndothelial CellsEndothelinEndothelin ReceptorEndothelin Receptor AntagonistEndothelin-1EndotheliumEventExperimental Autoimmune EncephalomyelitisExtravasationFDA approvedGeneticHistologicHumanHypertensionHypoxiaImageImmuneImmunologicsInfiltrationInflammatoryKnockout MiceLabelLesionLeukocyte TraffickingLeukocytesLinkLocationMacrophageMediatingMicrogliaMicroscopyModelingMolecularMolecular ProfilingMultiple SclerosisMultiple Sclerosis LesionsMusNeurologic SymptomsNumbnessParalysedPathologyPathway interactionsPatientsPeptidesPeripheralPropertyReceptor InhibitionRegulationRelapseRoleSeverity of illnessSignal TransductionSiteSpinal CordSpinal Cord LesionsStrokeSystemT-LymphocyteTestingTherapeuticTimeTissue BanksTissuesValidationVascular Endothelial CellVascular Endotheliumantagonistaxon injuryblood-brain barrier disruptionbrain tissuecell typedrug repurposingexperimental studyglial activationhuman tissuehypertension treatmentimaging studyimmune cell infiltratein vivoin vivo imaginginhibitormigrationmonocytemultiple sclerosis patientmultiple sclerosis treatmentneuroinflammationneuron losspharmacologicpre-clinicalpreventreceptorreceptor expressionrecruittwo-photonvascular abnormalityvasoconstriction
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
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(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:
10397055 - 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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