CYTOKINES, BEHAVIOR, AND MENTAL HEALTH

细胞因子、行为和心理健康

• 批准号: 6538702
• 负责人: Keith W Kelley
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6538702
• 关键词: BCL2 gene /protein; JAK kinase; behavior; behavioral /social science research tag; cysteine endopeptidases; cytokine; cytokine receptors; enzyme activity; gene induction /repression; immunoregulation; insulinlike growth factor; interleukin 1; interleukin 10; interleukin 4; laboratory mouse; mental health; phosphatidylinositol 3 kinase; psychoneuroimmunology; tachykinin; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION: (Applicant's Abstract): Individuals suffering from CNS-related pathologies, such as AIDS-related dementia and Alzheimer's disease, display a variety of behavioral and neurological symptoms including memory loss, lack of motivation and deterioration of motor functions. The proinflamatory cytokines TFNa and IL-1b are expressed in the brain in response to these diseases as well as to other insults, such as stroke, trauma, and peripheral inflammation. The potent anti-inflammatory cytokines IL-4 and IL-10 have recently been localized to the CNS, and the emerging idea is that both acute and chronic inflammatory pathologies are regulated by the balance of proinflammatory and anti-inflammatory cytokines in the brain. The investigators' preliminary data showing the IL-4 and IGF-I are active in the CNS to inhibit sickness behavior induced by centrally administered LPS support this concept. Receptors for both IL-4 and IGF-I utilize a cytoplasmic docking molecule known as Insulin-Receptor Substrate-1 (IRS-1) or IRS-2 (formally known as IL-4 receptor phosphorylated substrate). The cytoplasmic docking molecules activate Phosphatidylinositol 3-Kinase (PI 3-kinase), an enzyme recently shown to be critical in protecting against cellular insults and promoting the survival of many cells, including neurons and perhaps glia. The investigators hypothesize that activation of the IRS/PI 3-kinase proteins is a common element int he signaling pathways utilized by receptors for anti-inflammatory cytokines in the CNS, and that this activations pathway is inhibited by TNFa and IL-1b. Unfortunately, the localization, expression, activation (tyrosine phosphorylation) and inhibition (serine phosphorylation) of IRS proteins in the CNS have not been identified. The investigators indicate that they now have strong preliminary data showing that both IRS-1 and IRS-2 are expressed in primary mouse glia and neurons and that IL-4, IL-10, and IGF-I activate PI 3-kinase in glial cells. The possibility that proinflammatory cytokines can directly inhibit the protective actions of anti-inflammatory cytokines in the brain would be a pivotal discovery. Indeed, IRS-recruited PI 3-kinase activity may be a critical intermediate signaling molecule in this process and is likely to provide a novel target for intervention in neuropathologies. The investigators indicate that they have developed all of the techniques and generated preliminary data to support the hypothesis of a common IRS/PI 3-kinase signaling pathways by which proinflammatory cytokines antagonize the activities of anti-inflammatory cytokine receptors in the CNS. These experiments are needed to understand the critical signaling molecules that are likely to regulate the events that lead to debilitating and costly inflammatory afflictions in the brain.

描述：（申请人摘要）：患有以下疾病的个人 中枢神经系统相关疾病，例如艾滋病相关痴呆症和阿尔茨海默氏症 疾病，表现出各种行为和神经系统症状，包括 记忆丧失、缺乏动力和运动功能恶化。 这 促炎细胞因子 TFNa 和 IL-1b 在大脑中表达 对这些疾病以及其他侮辱的反应，例如中风， 外伤、周围炎症。 有效的抗炎细胞因子 IL-4和IL-10最近已定位于中枢神经系统，并且新兴的 想法是急性和慢性炎症病理都受到调节 通过体内促炎细胞因子和抗炎细胞因子的平衡 脑。 研究人员的初步数据显示 IL-4 和 IGF-I 是 活跃于中枢神经系统，抑制中枢神经系统诱发的疾病行为 管理的 LPS 支持这一概念。 IL-4 和 IGF-I 受体 利用称为胰岛素受体底物-1 的细胞质对接分子 (IRS-1) 或 IRS-2（正式名称为 IL-4 受体磷酸化底物）。 细胞质对接分子激活磷脂酰肌醇 3-激酶 (PI 3-激酶），一种最近被证明对于预防感染至关重要的酶 细胞损伤并促进许多细胞（包括神经元）的存活 也许还有神经胶质细胞。 研究人员假设激活 IRS/PI 3-激酶蛋白是信号通路中的常见元件 被中枢神经系统中的抗炎细胞因子受体利用，并且 该激活途径被 TNFa 和 IL-1b 抑制。 不幸的是， 定位、表达、激活（酪氨酸磷酸化）和 中枢神经系统中IRS蛋白的抑制（丝氨酸磷酸化）尚未被证实 确定。 调查人员表示，他们现在拥有强大的 初步数据表明 IRS-1 和 IRS-2 在原代细胞中均表达 小鼠神经胶质细胞和神经元，IL-4、IL-10 和 IGF-I 激活 PI 3 激酶 在神经胶质细胞中。 促炎细胞因子可能直接 抑制大脑抗炎细胞因子的保护作用 将是一个关键的发现。 事实上，IRS 招募了 PI 3 激酶活性 可能是该过程中关键的中间信号分子 可能为神经病理学干预提供新的靶点。 这 研究人员表示他们已经开发了所有技术并且 生成初步数据来支持共同 IRS/PI 的假设 拮抗促炎细胞因子的 3-激酶信号通路 中枢神经系统中抗炎细胞因子受体的活性。 这些 需要进行实验来了解关键的信号分子 可能会监管导致衰弱和代价高昂的事件 大脑炎症。