CYTOKINE REGULATION OF PROENKEPHALIN GENE EXPRESSION

脑啡肽原基因表达的细胞因子调节

• 批准号: 6104151
• 负责人: STEVEN E. HYMAN
• 金额: $ 26.59万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6104151
• 关键词: astrocytes; biological models; biological signal transduction; cytokine; endogenous opioid; enkephalins; gene expression; genetic regulation; genetic transcription; genetically modified animals; glia; hypothalamus; interleukin 1; laboratory mouse; laboratory rat; leukemia inhibitory factor; messenger RNA; model design /development; neurophysiology; northern blottings; second messengers; tissue /cell culture

Cytokines, which have long been known to regulate immune function and hematopoiesis, have recently been shown to exert powerful effects on neural gene expression, proliferation, and survival. Indeed the boundaries between peptides classified as cytokines and as neurotrophic factors has been increasingly blurred. For example, cytokines such as interleukin-1=DF (IL-1=DF) which act in the periphery to modulate the immune response, act within the hypothalamus to regulate overall organismic adaptations to infection, inflammation, and stress. Other cytokines, such as leukemia inhibitory factor (LIF), appear to be involved in the adaptation of the nervous system to injury, and are closely related to factors involved in neuronal survival and phenotype determination. Little is known to date about the molecular mechanisms by which cytokines regulate transcription of neural genes, and even less is known about the interactions among cytokine and neurotransmitter signaling pathways. The proenkephalin gene, which encodes the opioid peptides met- and leu-enkephalin, has served as an important model of transcriptional regulation in the nervous system; therefore much is known about proenkephalin gene structure and regulation. Because proenkephalin gene expression is regulated not only by neurotransmitters and drugs of abuse, but also by multiple cytokines, including both IL-1=DF and LIF, we propose to use the proenkephalin gene as = a model to elucidate the molecular actions of these representative and physiologically significant cytokines in the nervous system. We propose to use primary cultures of glia and hypothalamic neurons and the hypothalamus in intact animals, including transgenic mice, to study cytokine signalling pathways, their interactions with neurotransmitter signaling pathways, and their modulation by opioids. The resulting information should contribute, in addition, to our understanding of interactions between the nervous system and the immune system, and of the potential impact of drugs of abuse on these interactions, as may occur in active drug abusers with AIDS.

细胞因子长期以来一直被认为可以调节免疫功能 最近被证明对造血作用具有强大的作用 神经基因表达、增殖和存活。确实有界限 分类为细胞因子和神经营养因子的肽之间 已经越来越模糊了。例如，细胞因子如interleukin-1=DF (IL-1=DF) 在外周发挥作用，调节免疫反应， 在下丘脑内调节整体有机体适应 感染、炎症和压力。其他细胞因子，例如白血病 抑制因子（LIF），似乎参与了适应 神经系统损伤，与相关因素密切相关 神经元存活和表型测定。迄今为止知之甚少 关于细胞因子调节转录的分子机制 神经基因之间的相互作用，人们对它们之间的相互作用知之甚少。 细胞因子和神经递质信号传导途径。脑啡肽原基因， 它编码阿片肽甲硫氨酸和亮氨酸脑啡肽，已被用作 神经系统转录调控的重要模型； 因此，人们对脑啡肽原基因的结构和调控了解很多。 因为脑啡肽原基因表达不仅受 神经递质和滥用药物，而且还受到多种细胞因子的影响， 包括IL-1=DF和LIF，我们建议使用脑啡肽原基因 as = 阐明这些代表的分子行为的模型 以及神经系统中具有生理意义的细胞因子。我们 建议使用神经胶质细胞和下丘脑神经元的原代培养物 研究完整动物（包括转基因小鼠）的下丘脑 细胞因子信号通路及其与神经递质的相互作用 信号通路及其阿片类药物的调节。由此产生的 此外，信息还应有助于我们理解 神经系统和免疫系统之间的相互作用以及 滥用药物对这些相互作用的潜在影响，可能发生在 患有艾滋病的活跃吸毒者。