Neural estrogen synthesis by astrocytic aromatization, and neuroinflammation.

通过星形细胞芳香化和神经炎症合成神经雌激素。

• 批准号: 8401792
• 负责人: COLIN J SALDANHA
• 金额: $ 18.12万
• 依托单位: AMERICAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401792
• 关键词: Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Aromatase; Aromatase Inhibitors; Astrocytes; Autophagocytosis; Behavior; Behavioral Assay; Biological Preservation; Brain; Brain Injuries; Cells; Chronic; Data; Down-Regulation; Endotoxins; Estrogens; Event; Excision; Exposure to; Genetic Transcription; Health; Hormones; Huntington Disease; IL1R1 gene; IL6 gene; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Knockout Mice; Mechanics; Microglia; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuropathy; Organ; Parkinson Disease; Peripheral; Physiological; Process; RNA Interference; Relative (related person); Role; Severities; Signal Transduction; Steroids; Stroke; TNF gene; Testing; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Wild Type Mouse; brain tissue; cytokine; indexing; neural circuit; neuroinflammation; novel; prevent; relating to nervous system; research study; therapy development

DESCRIPTION (provided by applicant): Chronic neuroinflammation contributes to neuropathy and is implicated in a number of serious health conditions such as Stroke, Parkinson's and Alzheimer's disease. Emerging evidence strongly supports an anti-inflammatory role for circulating estrogens (E) since removal and replacement of this steroid dramatically exacerbates and mitigates several indices of inflammation respectively. Indeed, E-administration decreases the expression and secretion of several pro-inflammatory cytokines including IL1, IL6 and TNF?. The vertebrate brain responds to mechanical perturbation or endotoxin with a rapid increase in cytokine expression in microglia and aromatase (E- synthase) expression in reactive astrocytes. Importantly, microglial cytokine induction occurs prior to astrocytic aromatase expression suggesting that cytokines may induce the expression of aromatase in reactive glia. Given the well-studied anti-inflammatory role of peripheral E, we propose that neural E, via glial aromatization, may serve as a rapidly induced and potent anti-inflammatory signal in the vertebrate brain. More specifically, we hypothesize that cytokines rapidly induce sustained glial aromatase expression and consequent E synthesis, which in turn, causes a decrease in cytokines. This down-regulation prevents chronic exposure of neural tissue to the deleterious effects of prolonged cytokine secretion. To elucidate and hone this model we will use a molecular approach and behavioral assays to test the role of specific pro-inflammatory cytokines in the induction of aromatase transcription following central or peripheral endotoxin administration. Next, using a pharmacological inhibitor of aromatase, we will test the role of aromatization in the mitigation of cytokine expression and sickness behavior following central endotoxin administration. Taken together these experiments will explore an exciting new role for pro-inflammatory cytokines in the induction of encephalic, glial aromatization and further, a mechanism whereby cytokine activity is curtailed by neural E-provision. These data are necessary for the development of therapies that target and prevent inflammatory processes, thereby reducing the severity of neurodegenerative disease. PUBLIC HEALTH RELEVANCE: Chronic inflammation may contribute to devastating neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, Huntington's chorea and Stroke. Prolonged exposure to inflammatory secretions such as cytokines can result in autophagy and the destruction of important and necessary cells, tissues and organs including the brain. Preventing chronic inflammation may be one strategy towards mitigating neural degeneration and promoting the preservation of neural circuits. Notably, several peripheral hormones, including the estrogens (E) are potent anti-inflammatory agents with established roles in the dampening of cytokine secretion and other inflammatory events. This proposal will explore an exciting, novel mechanism of E-provision directly within the brain. Specifically, while the up-regulation of aromatase (E-synthase) in reactive astrocytes following brain damage and/or the exposure to inflammagens is well established, what signals responsible for the initiation of aromatase transcription is completely unknown. Further, the physiological consequences of glial-derived E are only beginning to be revealed. We propose that pro- inflammatory cytokines may initiate aromatase expression and this induction is necessary to quell prolonged cytokine expression and sickness behavior. This reduction in the chronic exposure of brain tissue to cytokines may prevent degeneration and/or other deleterious effects of sustained neuroinflammation.

描述(申请人提供)：慢性神经炎有助于神经病变，并与许多严重的健康状况有关，如中风、帕金森氏症和阿尔茨海默氏症。新出现的证据有力地支持了循环雌激素(E)的抗炎作用，因为移除和替换这种类固醇可以显着地分别加剧和减轻几种炎症指标。事实上，电子政务减少了几种促炎细胞因子的表达和分泌，包括IL1、IL6和TNF？脊椎动物的大脑对机械扰动或内毒素做出反应，小胶质细胞中细胞因子的表达迅速增加，反应性星形胶质细胞中芳香化酶(E-Synthase)的表达迅速增加。重要的是，小胶质细胞细胞因子的诱导发生在星形细胞芳香酶表达之前，这表明细胞因子可能诱导反应性胶质细胞芳香酶的表达。鉴于外周E的抗炎作用已被充分研究，我们认为，神经E通过神经胶质芳构化，可能在脊椎动物的大脑中作为一种快速诱导和有效的抗炎信号。更具体地说，我们假设细胞因子迅速诱导持续的胶质芳香酶表达和随后的E合成，这反过来导致细胞因子的减少。这种下调可以防止神经组织长期暴露在细胞因子分泌过长的有害影响中。为了阐明和完善这一模型，我们将使用分子方法和行为分析来测试特定的促炎细胞因子在中枢或外周内毒素注射后诱导芳香酶转录中的作用。接下来，我们将使用一种芳香酶的药理抑制剂，测试芳构化在中枢性内毒素注射后减轻细胞因子表达和疾病行为方面的作用。综上所述，这些实验将探索促炎细胞因子在诱导脑、神经胶质芳构化中的令人兴奋的新作用，并进一步探索细胞因子活性被神经E-供应抑制的机制。这些数据对于开发针对和预防炎症过程的治疗方法是必要的，从而降低神经退行性疾病的严重程度。 公共卫生相关性：慢性炎症可能会导致毁灭性的神经退行性疾病，包括阿尔茨海默病、帕金森氏病、亨廷顿舞蹈症和中风。长期接触细胞因子等炎性分泌物会导致自噬，并破坏重要和必要的细胞、组织和器官，包括大脑。预防慢性炎症可能是减轻神经退行性变和促进神经回路保护的一种策略。值得注意的是，包括雌激素(E)在内的几种外周激素是有效的抗炎药，在抑制细胞因子分泌和其他炎症事件中具有既定的作用。这项提议将探索一种令人兴奋的、新颖的机制，直接在大脑中提供电子产品。具体地说，虽然脑损伤和/或暴露于炎性物质后反应性星形胶质细胞芳香化酶(E-Synthase)的上调是众所周知的，但什么信号负责启动芳香酶转录是完全未知的。此外，神经胶质来源的E的生理后果才刚刚开始被揭示。我们认为，促炎细胞因子可以启动芳香酶的表达，这种诱导对于平息细胞因子的长期表达和疾病行为是必要的。这种减少脑组织对细胞因子的慢性暴露可能会防止变性和/或持续神经炎症的其他有害影响。