GROWTH FACTOR SIGNAL TRANSDUCTION AND NEUROTRANSMISSION

描述(摘自申请人的摘要)： 现在有大量证据表明，生长因子和细胞因子 涉及神经病理和精神障碍；确切地说是如何 这些影响是通过中介来实现的，目前尚不清楚。胰岛素和其他生长因子 众所周知，它可以调节新陈代谢和分化/增殖， 分别进行了分析。然而，在分化的神经元上，胰岛素和 细胞因子可能是调节神经传递的物质。一个必要的前提条件 了解生长因子/细胞因子的作用是识别分子 这些因子对神经元发挥生物学作用的机制。这个 这项建议的目的是确定信号转导途径，并 生长因子(胰岛素)调节突触的分子机制 传递(增强NMDA受体活性)该模型系统是 选择它是因为它具有显著的神经病理学和精神病学 这意味着什么。Nmda受体被认为在各种疾病中起关键作用。 (例如，艾滋病痴呆症、癫痫、中风、精神分裂症、肌萎缩侧索硬化症等)，因此 调节它们的因素可能有助于神经学和精神病学 紊乱，从而解释了观察到胰岛素改善症状的原因 阿尔茨海默氏症和精神分裂症。我们的具体实验目标 是：1)使用药剂和电生理技术 识别介导的受体类型和信号转导途径 胰岛素增强大鼠海马片和海马区NMDA受体反应 在非洲爪蛙卵母细胞中表达重组NMDA受体；2)使用突变的 重组胰岛素受体和胰岛素受体底物(IRS-1) 确定启动胰岛素受体系统的哪些信号组件 NMDA受体反应的调节；3)识别胰岛素诱导的 大鼠海马神经元NMDA受体上的磷酸化(或去磷酸化)位点 然后使用定点突变来确定这些基因的作用 非洲爪哇卵母细胞NMDA受体功能上的磷酸化位点。同舟共济 这些研究确定了特定的细胞信号通路和 胰岛素调节NMDA受体活性的分子机制。这 知识将作为确定胰岛素在以下几个方面的作用的基础 大脑功能和神经紊乱的方面。这些研究还将 生成关于哪些其他生长因子/细胞因子系统起中介作用的预测 类似的效果，并将产生可以测试这一作用的标记 神经和精神疾病中的信号系统。

DESCRIPTION (from applicant's abstract): There is now a significant body of evidence that growth factors and cytokines are involved in neuropathological and psychiatric disorders; precisely how these effects are mediated is unknown. Insulin and other growth factors are well known to modulate metabolism and differentiation/proliferation, respectively. However, on differentiated neurons, the major role of insulin and cytokines may be, to modulate neurotransmission. A necessary prerequisite for understanding growth factor/cytokine actions is to identify the molecular mechanisms by which these factors exert their biological action on neurons. The objective of this proposal is to determine the signal transduction pathway and, molecular mechanisms by which a growth factor (insulin) regulates synaptic transmission (potentiation of NMDA receptor activity)This model system was chosen because it has significant neuropathological and psychiatric implications. NMDA receptors are thought to play a key role various diseases (e.g. AIDS dementia, epilepsy, stroke, schizophrenia, ALS, and others), thus factors that regulate them may contribute to neurological and psychiatric disorders, and thus account for the observations that insulin improves symptoms in both Alzheimer's disease and schizophrenia. Our specific experimental goals are: 1) to use pharmacological agents and electrophysiological techniques to identify the receptor type and signal transduction pathways that mediate insulin potentiation of NMDA receptor responses in rat hippocampal slices and in Xenoptis oocytes expressing recombinant NMDA receptors; 2) to use mutated recombinant insulin receptors and insulin receptor substrates (IRS-1) to identify which signaling components of the insulin receptor system initiatee modulation of NMDA receptor responses; 3) to identify the insulin-induced phosphorylation (or dephosphorylation) sites on rat hippocampal NMDA receptors and then use site-directed mutagenesis to determine the role of these phosphorylation sites on NMDA receptor function in Xenopus oocytes. Together these studies win identify the specific cellular signaling pathways and molecular mechanisms by which insulin modulates NMDA receptor activity. This knowledge would serve as a basis for determining insulin's role in several aspects of brain function and neurological disorders. These studies would also generate predictions about which other growth factor / cytokine systems mediate similar effects and would generate markers that could test the role of this signaling system in neurological and psychiatric disorders.