CYTOKINES, BEHAVIOR, AND MENTAL HEALTH

描述：(申请人摘要)：患有 中枢神经系统相关病理，如艾滋病相关性痴呆和阿尔茨海默氏症 疾病，表现出各种行为和神经症状，包括 记忆力丧失，缺乏动力，运动功能恶化。这个 促炎细胞因子TFNa和IL-1b在脑内表达 对这些疾病的反应以及对其他侮辱，如中风， 创伤和外周炎症。强效抗炎细胞因子 IL-4和IL-10最近已定位于中枢神经系统，新兴的 想法是急性和慢性炎症病理都是受调控的 通过促炎和抗炎细胞因子在血管内的平衡 大脑。调查人员的初步数据显示，IL-4和IGF-I是 活跃于中枢神经系统以抑制中枢诱发的疾病行为 被管理的脂多糖支持这一概念。IL-4和IGF-I受体 利用一种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)。 胞质对接分子激活磷脂酰肌醇3-激酶(PI 3-激酶)，这是一种最近被证明在预防 细胞侮辱和促进包括神经元在内的许多细胞的存活 也许还有神经胶质细胞。调查人员假设激活的是 IRS/PI3-K蛋白是信号转导途径中的共同元件 被中枢神经系统中的抗炎细胞因子受体利用，并且 这一激活途径被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 已确认身份。调查人员表示，他们现在有很强的 初步数据显示，IRS-1和IRS-2都在原代表达 小鼠神经胶质细胞和神经元及IL-4、IL-10和IGF-I激活PI3-激酶的研究 在神经胶质细胞中。促炎细胞因子可以直接 抑制抗炎细胞因子在脑内的保护作用 将是一项关键的发现。事实上，IRS招募的PI 3-激酶活性 可能是这一过程中的关键中间信号分子，并且 很可能为神经病理学干预提供一个新的靶点。这个 调查人员表示，他们已经开发出了所有的技术和 生成初步数据以支持共同IRS/PI的假设 促炎症细胞因子拮抗的3-激酶信号通路 中枢神经系统抗炎细胞因子受体的活性。这些 需要实验来了解关键的信号分子 可能会对导致衰弱和代价高昂的事件进行监管 大脑中的炎症性疾病。

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.