IL-1 in Protection and Injury
IL-1 的保护和损伤作用
基本信息
- 批准号:8731981
- 负责人:
- 金额:$ 39.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-07-18 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAnabolismAnimalsAntioxidantsAstrocytesBiologicalBrainBrain InjuriesCerebral IschemiaCerebrumComplementCysteineCystineDataDevelopmentEconomic BurdenEmotionalExcitatory Amino Acid ReceptorsGenesGeneticGlutamatesGlutathioneGoalsGrantHomeostasisHypoxiaIn VitroInflammatoryInjuryInterleukin-1Ischemic PenumbraKnowledgeLaboratoriesLightLinkMediatingMessenger RNAMicrogliaModelingMolecularMorbidity - disease rateMusNatureNeuronal InjuryNeuronsOxidation-ReductionOxidative StressPlayPredispositionProbabilityPublic HealthReceptor SignalingRegulationResearchResistanceRoleSignal TransductionSpecificityStrokeSubstrate SpecificitySystemTestingTimeTissuesTrans-ActivatorsUp-Regulationantiporterexcitotoxicityextracellularin vitro Modelin vivoin vivo Modelinjurednew therapeutic targetnovelpublic health relevancerepairedresponsestoichiometrytherapeutic targetuptake
项目摘要
DESCRIPTION (provided by applicant): Injury to the brain caused by cerebral ischemia is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. During the last grant period our laboratory demonstrated that astrocyte-mediated alterations in system xc- (cystine/glutamate antiporter) activity contributes to the development and progression of inflammatory (IL-1beta-enhanced) hypoxic neuronal injury -a model of the ischemic penumbra. Despite this, new preliminary data demonstrate that IL-1beta-mediated upregulation of the same molecule, system xc-, can confer protection against oxidative insults. We speculate that IL-1beta upregulation of astrocyte system xc- may have evolved as a protective mechanism to counteract oxidative stress in injured tissue. However, this increase becomes maladaptive in the setting of compromised glutamate uptake, which occurs in the setting of our hypoxia model in vitro and stroke in vivo. The concept that IL-1beta and system xc- are at the crossroads of injury and protection is particularly intriguing. Studies to systematically and empirically address these ideas, as well as, to elucidate
the regulation of the transporter by IL-1beta at the molecular level are solely needed. Thus, the objectives of this following 5 yr research plan of study are as follows: 1) To determine the mechanism by which IL-1beta regulates astrocyte system xc- expression. State of the art molecular biological approaches will be utilized to assess whether IL-1beta regulates xCT mRNA at the transcriptional and/or post-transcriptional level and to identify the cis and trans-acting factors responsible for the induction and/or stabilization of xCT message. 2) To determine the functional consequence of enhanced system xc- activity. The goal of this aim is to determine whether the IL-1beta-mediated enhancement of system xc- activity, a priori, increases GSH content and confers a selective resistance to oxidative injury under conditions where glutamate uptake is competent both in vitro and in vivo. 3) Using genetic approaches, studies will be undertaken to determine the extent to which IL-1beta signaling regulates system xc- expression following cerebral ischemic injury with the direct question as to whether loss of system xc- function either globally, or in astrocytes specifically, can alter the susceptibility of mouse brai to cerebral ischemic damage. Understanding the regulation of system xc- by IL-1beta is necessary so that we may use this information to devise strategies to harness the beneficial effects (i.e. to
increase GSH levels to reduce oxidative injury), and when appropriate, to employ strategies to reduce its activity to decrease the probability of excitotoxic neuronal injury (i.e. under conditios where glutamate uptake is impaired).
描述(由申请人提供):脑缺血引起的脑损伤是一个主要的公共卫生问题。研究已经确定与脑缺血相关的脑损伤是由兴奋性氨基酸受体的过度刺激、氧化应激以及炎症因子介导的。在上一个资助期间,我们的实验室证明了星形胶质细胞介导的系统xc-(胱氨酸/谷氨酸反向转运蛋白)活性的改变有助于炎症(IL-1 β增强)缺氧神经元损伤的发展和进展-缺血半暗带的模型。尽管如此,新的初步数据表明,IL-1 β介导的上调相同的分子,系统xc-,可以提供保护免受氧化损伤。我们推测星形胶质细胞系统xc-的IL-1 β上调可能是一种保护机制,以抵消损伤组织中的氧化应激。然而,这种增加在受损的谷氨酸摄取的情况下变得不适应,这发生在我们的体外缺氧模型和体内中风的情况下。IL-1 β和系统xc-处于损伤和保护的十字路口的概念特别有趣。研究系统地和经验地解决这些想法,以及,阐明
仅需要IL-1 β在分子水平上调节转运蛋白。因此,本研究的目标是:1)确定IL-1 β调节星形胶质细胞系统xc-表达的机制。将利用最先进的分子生物学方法评估IL-1 β是否在转录和/或转录后水平调节xCT mRNA,并鉴定负责xCT信息诱导和/或稳定的顺式和反式作用因子。2)确定增强系统xc-活性的功能后果。本研究的目的是确定IL-1 β介导的系统xc-活性增强是否先验地增加GSH含量,并在体外和体内谷氨酸摄取均胜任的条件下赋予对氧化损伤的选择性抗性。3)利用遗传学方法,将进行研究以确定IL-1 β信号传导在多大程度上调节脑缺血损伤后系统xc-表达,直接的问题是系统xc-功能的丧失,无论是全局性的,还是星形胶质细胞特异性的,是否可以改变小鼠脑对脑缺血损伤的易感性。了解IL-1 β对系统xc-的调节是必要的,这样我们就可以利用这些信息来设计策略,利用有益的效果(即,
增加GSH水平以减少氧化损伤),并且在适当时,采用降低其活性的策略以降低兴奋性毒性神经元损伤的可能性(即在谷氨酸摄取受损的条件下)。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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SANDRA J HEWETT的其他文献
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{{ truncateString('SANDRA J HEWETT', 18)}}的其他基金
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
- 批准号:
10214720 - 财政年份:2020
- 资助金额:
$ 39.66万 - 项目类别:
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
- 批准号:
10357770 - 财政年份:2018
- 资助金额:
$ 39.66万 - 项目类别:
Investigating the role of system xc- in glutamate, glutathione and synapse homeostasis in vivo
研究系统 xc- 在体内谷氨酸、谷胱甘肽和突触稳态中的作用
- 批准号:
10116499 - 财政年份:2018
- 资助金额:
$ 39.66万 - 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
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8302237 - 财政年份:2011
- 资助金额:
$ 39.66万 - 项目类别:
Constructing a Conditional Slc7a11 (xCT) Null Mouse
构建条件 Slc7a11 (xCT) 空鼠标
- 批准号:
8203292 - 财政年份:2011
- 资助金额:
$ 39.66万 - 项目类别:
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