RAS AND NEURONAL GENE REGULATION BY CNTF

了解神经系统发育的潜在机制 系统是神经生物学的基本目标之一。的 交感神经元中的肾上腺素能-胆碱能开关代表了一种 经过充分研究的生理相关发育模型系统 其中多个酶和神经肽基因被 良好表征的分化因子。一个这样的因素纤毛 神经营养因子（CNTF）参与了 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， 关于介导CNTF作用的细胞内步骤， 相关细胞因子对基因表达的影响。我们最近的发现和 其他人支持ras原癌基因产物 在这些细胞因子对 神经元分化 我建议系统地检验这一假设，首先通过 在法规中描述Ras激活的要求 CNTF及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（LIF）。 接下来我们 我将剖析这一规定的组成部分，重点是如何 CNTF和LIF激活Ras，然后依次研究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 在发育和疾病的神经元模型中的作用，包括 培养的交感神经和黑质神经元。

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.