IL-1 in Protection and Injury

IL-1 的保护和损伤作用

基本信息

批准号：
9093848
负责人：
SANDRA J HEWETT
金额：
$ 35.14万
依托单位：
SYRACUSE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9093848
关键词：
Address Anabolism Animals Antioxidants Astrocytes Biological Brain Brain Injuries Cerebral Ischemia Cerebrum Complement Cysteine Cystine Data Development Economic Burden Emotional Excitatory Amino Acid Receptors Genes Glutamates Glutathione Goals Grant Health Homeostasis Hypoxia In Vitro Inflammatory Injury Interleukin-1 Ischemic Penumbra Knowledge Laboratories Light Link Mediating Messenger RNA Microglia Modeling Molecular Morbidity - disease rate Mus Nature Neuronal Injury Neurons Oxidation-Reduction Oxidative Stress Play Predisposition Probability Public Health Receptor Signaling Regulation Research Resistance Role Signal Transduction Specificity Stroke Substrate Specificity System Testing Time Tissues Trans-Activators Up-Regulation antiporter cerebral ischemic injury excitotoxicity extracellular genetic approach in vitro Model in vivo in vivo Model injured new therapeutic target novel repaired response stoichiometry stroke treatment therapeutic target uptake

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）：脑缺血引起的大脑受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通过过度刺激兴奋性氨基酸受体，氧化应激以及炎症因子介导的。在最后一个赠款期间，我们的实验室表明，星形胶质细胞介导的系统XC-（胱氨酸/谷氨酸抗植物）活性的改变有助于炎症性（IL-1BETA增强）低氧神经损伤的发展和进展-A缺血性Penumbra模型。尽管如此，新的初步数据表明，IL-1BETA介导的同一分子的上调System XC-可以赋予氧化损伤的保护。我们推测，星形胶质细胞系统的IL-1Beta上调XC-可能已演变为抵消受伤组织中氧化应激的保护机制。然而，在受损的谷氨酸摄取的情况下，这种增加变得不良适应性，这发生在我们在体外和中风的缺氧模型的情况下发生。 IL-1Beta和System XC-处于伤害和保护的十字路口的概念特别有趣。研究这些思想以及阐明这些想法的研究仅需要通过IL-1Beta在分子水平上调节转运蛋白。因此，此以下5年研究计划的目标如下：1）确定IL-1Beta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来评估IL-1BETA是否在转录和/或转录后水平调节XCT mRNA，并确定负责XCT信息诱导和/或稳定的顺式和跨性别因素。 2）确定增强系统XC活性的功能后果。该目标的目的是确定IL-1BETA介导的系统XC活性的增强，先验性，提高GSH含量，并在谷氨酸摄取效果均具有体外和体内均能胜任的条件下对氧化损伤的选择性抗性。 3）使用遗传方法，将进行研究，以确定脑缺血性损伤后IL-1BETA信号调节系统XC-表达的程度，直接问题，即在全球范围内还是在全球范围内或在星形胶质细胞中丧失，或可以改变小鼠对脑缺血性损伤的敏感性。必须了解IL-1Beta对系统XC-的调节，因此我们可以使用此信息来制定策略来利用有益效果（即增加GSH水平以减少氧化损伤），并在适当的情况下采用策略来减少其活性以降低兴奋性神经元损伤的可能性（即在谷氨酸摄取受损的Conditios下）。