IL-1 in Protection and Injury

IL-1 的保护和损伤作用

• 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
• 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

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。研究表明，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。在上一次资助期间，我们的实验室证明，星形胶质细胞介导的系统 xc-（胱氨酸/谷氨酸逆向转运蛋白）活性的改变有助于炎症（IL-1β 增强）缺氧神经元损伤（缺血半影模型）的发生和进展。尽管如此，新的初步数据表明，IL-1β 介导的同一分子（系统 xc-）的上调可以提供针对氧化损伤的保护。我们推测星形胶质细胞系统 xc- 的 IL-1β 上调可能已进化为一种保护机制，以对抗受损组织中的氧化应激。然而，这种增加在谷氨酸摄取受损的情况下变得适应不良，这种情况发生在我们的体外缺氧模型和体内中风的情况下。 IL-1beta 和系统 xc- 处于损伤和保护十字路口的概念特别有趣。研究系统地、实证地解决这些想法，并阐明 仅需要IL-1β在分子水平上对转运蛋白的调节。因此，接下来的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。最先进的分子生物学方法将用于评估IL-1β是否在转录和/或转录后水平调节xCT mRNA，并鉴定负责诱导和/或稳定xCT信息的顺式和反式作用因子。 2) 确定增强的系统xc-活性的功能结果。该目的的目的是确定 IL-1β 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有效的条件下赋予对氧化损伤的选择性抵抗力。 3) 使用遗传方法，将进行研究以确定脑缺血损伤后IL-1β信号传导调节系统xc表达的程度，直接问题是系统xc功能的丧失，无论是整体的，还是在星形胶质细胞中，是否会改变小鼠脑对脑缺血损伤的易感性。了解 IL-1beta 对系统 xc- 的调节是必要的，以便我们可以利用这些信息来设计策略来利用有益效果（即 增加 GSH 水平以减少氧化损伤），并在适当时采取策略降低其活性，以降低兴奋性毒性神经元损伤的可能性（即在谷氨酸吸收受损的情况下）。