Investigation of the Modulators of Cerebrovascular Coupling
脑血管耦合调节剂的研究
基本信息
- 批准号:10018684
- 负责人:
- 金额:$ 62.72万
- 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:2-arachidonylglycerolAftercareAnimalsAnti-inflammatoryArachidonic AcidsArchitectureAreaBlood VesselsBrainBrain DiseasesCallithrixCerebral IschemiaCerebrovascular CirculationCerebrovascular systemCharacteristicsCommunicationComplexCouplingDataDevelopmentDigit structureDiseaseEndocannabinoidsEndothelin-1Energy SupplyEnzyme Inhibitor DrugsExcisionExhibitsFaceGoalsHealthcareHomeostasisHumanHypertensionInbred SHR RatsIndividualInfarctionInflammatoryInjectionsInvestigationIschemiaIschemic StrokeLeadLeftLeukotrienesMagnetic Resonance ImagingMapsMeasuresMicrogliaModelingMolecularMonoacylglycerol LipasesNational Institute of Neurological Disorders and StrokeNeurogliaNeurological outcomeNeuronsOrganPathway interactionsPeptidesPrimatesPropertyProstaglandinsRegulationResearchResistanceResolutionRodentRoleSignal PathwaySignal TransductionStrokeTestingTimeTranslatingTreesUniversitiesVascular blood supplyWorkbasebrain dysfunctionbrain parenchymacannabinoid receptorcerebrovascularexperimental studyhemodynamicsimprovednervous system disorderneuroinflammationneuron lossneuropathologyneurovascular couplingneurovascular unitnormotensivenovelrelating to nervous systemresponsespatiotemporaltargeted treatmenttherapeutic targetvascular factorwasting
项目摘要
This is the final year of this project do to the departure of Afonso Silva from intramural NINDS to UNiversity of Pittsburgh. Dr. Koretsky has been acting section chief since Dr. Silva left. The project will be terminated in the next FY. We want to understand how alterations in cortical functional domains induced by stroke lead to changes in the hemodynamic response to increased neural activity. This will allow us to refine the notion that the cerebrovasculature is built to support the functional organization of the cortex, and enable development of a better model of inferring about the flow of neuronal communication from careful analysis of the spatiotemporal features of the hemodynamic response. For this, we will develop focal ischemic models based on spatially targeted applications of vasoconstricting peptides such as endothelin-1 (ET-1) to test the relevance of different sub-regions of the cortex and, in particular, of individual functional areas (e.g. individual face patches or the representation of individual digits) in dictating the spatiotemporal characteristics of the hemodynamic response. We use high-resolution MRI of the cortical cytoarchitecture to plan and chose the target sub-domains within the cortex to be made ischemic, and compare the post-ischemia functional data with those obtained from the same animals pre-ischemia. We will also compare cerebrovascular resistance and vascular territory maps obtained at both states. Because the stroke area will be made small, it is possible that these maps will not change, but task-induced hemodynamic responses will be significantly different due to the region-selective death of neuronal cells caused by stroke. These experiments will provide a better understanding of how the architecture of the vascular tree influences the spatiotemporal features of the hemodynamic response.
OVer the past few years used the spontaneously hypertensive rat (SHR) and its normotensive control WKY to evaluate the effects of an intracortical injection of ET-1. ET-1 produces a larger infarct volume in SHR than in WKY. Both pre- and post-treatment of the animals with JZL184, a powerful and specific inhibitor of the enzyme monoacylglycerol lipase (MAGL) significantly reduces the infarct volume induced by ET-1, thus establishing that MAGL as an important therapeutic target for stroke. In addition, MAGL inhibition significantly improved neurological outcome post-ischemia. MAGL hydrolyzes 2-arachidonoyl glycerol (2-AG), the most abundant endogenous cannabinoid in the brain, into arachidonic acid (AA), an important precursor of pro-inflammatory prostaglandins and leukotrienes. 2-AG exhibits anti-inflammatory and neuroprotective properties not only through modulating the signaling of cannabinoid receptors, but also by controlling AA release. Thus we hypothesized that MAGL inhibition might be a novel anti-inflammatory and neuroprotective strategy for neurological disorders, including ischemic stroke. Inhibition of MAGL leads to suppressed neuroinflammation, as measured by a significant reduction in the number of activated microglia in the ischemic core. Thus, our results suggest that MAGL alone contributes to neuropathology of cerebral ischemia, and thus is a promising therapeutic target for the treatment of ischemic stroke. To validate the work in the primate brain, it will be exciting to reproduce the same above experiments in marmosets, and we intend to do so just as soon as we finish the rodent study.
今年是这个项目的最后一年,因为Afonso Silva从校内NINDS来到匹兹堡大学。科瑞茨基医生在席尔瓦医生离开后一直是代理科长。该项目将在下一个财政年度终止。我们想了解脑卒中引起的皮质功能域的改变是如何导致血液动力学对神经活动增加的反应发生变化的。这将使我们能够完善脑血管系统是为了支持皮层的功能组织而建立的这一概念,并使我们能够通过仔细分析血流动力学反应的时空特征,开发出更好的模型来推断神经元通信的流动。为此,我们将基于血管收缩肽(如内皮素-1 (ET-1))的空间靶向应用开发局灶性缺血模型,以测试皮层不同子区域的相关性,特别是单个功能区(例如单个面部斑块或单个手指的代表)在指示血流动力学反应的时空特征方面的相关性。我们使用高分辨率的皮层细胞结构MRI来规划和选择皮层内要缺血的目标亚域,并将缺血后的功能数据与缺血前的数据进行比较。我们还将比较两州的脑血管阻力和血管版图图。由于中风区域变小,这些地图可能不会改变,但由于中风引起的神经元细胞的区域选择性死亡,任务诱导的血流动力学反应将显著不同。这些实验将更好地理解血管树的结构如何影响血流动力学响应的时空特征。
项目成果
期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Assessing Cerebrovascular Reactivity in Carotid Steno-Occlusive Disease Using MRI BOLD and ASL Techniques.
- DOI:10.1155/2012/268483
- 发表时间:2012
- 期刊:
- 影响因子:2.7
- 作者:Leoni RF;Mazzetto-Betti KC;Silva AC;Dos Santos AC;de Araujo DB;Leite JP;Pontes-Neto OM
- 通讯作者:Pontes-Neto OM
Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.
- DOI:10.1161/strokeaha.117.019664
- 发表时间:2018-03
- 期刊:
- 影响因子:8.3
- 作者:Choi SH;Arai AL;Mou Y;Kang B;Yen CC;Hallenbeck J;Silva AC
- 通讯作者:Silva AC
The stability of the blood oxygenation level-dependent functional MRI response to motor tasks is altered in patients with chronic ischemic stroke.
慢性缺血性中风患者的血氧水平依赖性功能性 MRI 对运动任务反应的稳定性发生了改变。
- DOI:10.1161/strokeaha.110.590471
- 发表时间:2010
- 期刊:
- 影响因子:8.3
- 作者:Mazzetto-Betti,KelleyC;Leoni,RenataF;Pontes-Neto,OctavioM;Santos,AntonioC;Leite,JoaoP;Silva,AfonsoC;deAraujo,DraulioB
- 通讯作者:deAraujo,DraulioB
Dynamic magnetic resonance imaging of cerebral blood flow using arterial spin labeling.
使用动脉自旋标记对脑血流进行动态磁共振成像。
- DOI:10.1007/978-1-59745-543-5_13
- 发表时间:2009
- 期刊:
- 影响因子:0
- 作者:Silva,AfonsoC;Paiva,FernandoF
- 通讯作者:Paiva,FernandoF
Using manganese-enhanced MRI to understand BOLD.
- DOI:10.1016/j.neuroimage.2012.01.008
- 发表时间:2012-08-15
- 期刊:
- 影响因子:5.7
- 作者:Silva, Afonso C.
- 通讯作者:Silva, Afonso C.
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Afonso Silva其他文献
Afonso Silva的其他文献
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{{ truncateString('Afonso Silva', 18)}}的其他基金
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
7735329 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
8158225 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
8746820 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
8342262 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
9563139 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Investigation of the Modulators of Cerebrovascular Coupling
脑血管耦合调节剂的研究
- 批准号:
8158201 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
8940087 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Spatial-Temporal Characterization of The Hemodynamic Response to Neural Activity
神经活动血流动力学反应的时空特征
- 批准号:
9157534 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Investigation of the Modulators of Cerebrovascular Coupling
脑血管耦合调节剂的研究
- 批准号:
8342235 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
Investigation of the Modulators of Cerebrovascular Coupling
脑血管耦合调节剂的研究
- 批准号:
8557035 - 财政年份:
- 资助金额:
$ 62.72万 - 项目类别:
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