IL-1 in Protection and Injury

IL-1 的保护和损伤作用

• 批准号: 8885063
• 负责人: SANDRA J HEWETT
• 金额: $ 0.41万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885063
• 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; Genetic; 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; excitotoxicity; extracellular; in vitro Model; in vivo; in vivo Model; injured; new therapeutic target; novel; repaired; response; stoichiometry; 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(申请人提供)：脑缺血对大脑造成的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XC系统(胱氨酸/谷氨酸逆向转运体)活性的变化有助于炎症性(IL-1β增强的)缺氧性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-1β介导的同一分子系统XC-的上调可以提供对氧化侮辱的保护。我们推测，IL-1β上调星形胶质细胞系统XC-可能已经进化为一种保护机制，以对抗损伤组织中的氧化应激。然而，这种增加在谷氨酸摄取受损的环境中变得不适应，这发生在我们的体外低氧模型和体内中风模型的环境中。IL-1β和系统XC-处于损伤和保护的十字路口的概念特别耐人寻味。系统地和经验性地解决这些想法的研究，以及阐明 IL-1β在分子水平上对转运蛋白的调节是唯一需要的。因此，这项为期5年的研究计划的目标如下：1)确定IL-1β调节星形胶质细胞系统XC-表达的机制。最新的分子生物学方法将被用来评估IL-1β是否在转录和/或转录后水平调节XCT mRNA，并识别负责XCT信息的诱导和/或稳定的顺式和反式作用因子。2)确定系统XC活性增强的功能后果。其目的是确定在体外和体内谷氨酸摄取正常的条件下，IL-1β介导的系统XC活性的增强是否先验地增加了GSH的含量，并赋予了对氧化损伤的选择性抵抗。3)利用遗传学方法，研究IL-1β信号对脑缺血损伤后XC系统表达的调节程度，直接问题是XC系统功能的整体丧失或星形胶质细胞功能丧失是否会改变小鼠脑缺血损伤的敏感性。了解IL-1β对XC系统的调节是必要的，这样我们就可以利用这些信息来制定策略来利用有益的影响(即 提高谷胱甘肽水平以减少氧化损伤)，并在适当时采取减少其活性的策略，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)。