RAS AND NEURONAL GENE REGULATION BY CNTF

CNTF 对 RAS 和神经元基因的调控

• 批准号: 2259846
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 7.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2259846
• 关键词: antibody; cell cycle proteins; cell differentiation; cytokine; developmental neurobiology; gel mobility shift assay; gene expression; genetic mapping; genetic regulation; genetic transcription; growth factor receptors; guanine nucleotide binding protein; laboratory rat; migration inhibition factor; neurons; neuropeptides; neurotrophic factors; protein kinase C; protein tyrosine kinase; protooncogene; regulatory gene; substantia nigra; sympathetic ganglion; tissue /cell culture; vasoactive intestinal peptide

Understanding the mechanisms underlying development of the nervous system is one of the fundamental goals of neurobiology. The adrenergic-cholinergic switch in sympathetic neurons represents a well-studied, physiologically relevant developmental model system in whiCh multiple enzyme and neuropeptide genes are coregulated by well Characterized differentiation factors. One such factor ciliary neurotrophic factor (CNTF) has been implicated in the determination of neuronal phenotype and survival, and more recently in the therapy of neurodegenerative disease. However, little Is known about the intracellular steps that mediate the effects of CNTF and related cytokines on gene expression. Recent findings of ours and others support the hypothesis that the ras protooncogene product plays an important role in the effects of these cytokines on neuronal differentiation. I propose to systematically test this hypothesis, initially by characterizing the requirement for Ras activation in the regulation of neuronal gene transcription by CNTF and the related cytokine differentiation factor, leukemia inhibitory factor (LlF). Next, we will dissect the components of this regulation by focusing on how CNTF and LIF activate Ras, and then on how Ras activation in turn leads to neuropeptide gene transcription in R neuroblastoma cell line. Finally, we will investigate whether Ras mediates cytokine effects in neuronal models of development and disease, including cultured sympathetic and nigral neurons.

了解神经发育的潜在机制 系统是神经生物学的基本目标之一。这 交感神经元中的肾上腺素能-胆碱能开关代表 经过充分研究的、生理相关的发育模型系统 其中多种酶和神经肽基因由 明确表征的分化因素。其中之一就是睫状体 神经营养因子（CNTF）参与了测定 神经元表型和存活率，以及最近在 神经退行性疾病的治疗。然而，鲜为人知 关于介导 CNTF 作用的细胞内步骤和 相关细胞因子对基因表达的影响。我们的最新发现和 其他人支持 ras 原癌基因产物的假设 这些细胞因子在影响细胞因子的过程中发挥着重要作用 神经元分化。 我建议系统地检验这个假设，首先是 描述法规中 Ras 激活的要求 CNTF 和相关细胞因子对神经元基因转录的影响 分化因子、白血病抑制因子(LlF)。 接下来，我们 将通过重点关注如何剖析该法规的组成部分 CNTF和LIF激活Ras，接下来依次介绍Ras如何激活 导致 R 神经母细胞瘤细胞中神经肽基因转录 线。最后，我们将研究Ras是否介导细胞因子 对发育和疾病神经元模型的影响，包括 培养交感神经元和黑质神经元。