SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON SURVIVAL

说明(摘自申请者摘要)： 拟议的研究是为了阐明调节细胞死亡和 在发育中的哺乳动物中枢神经系统中存活。神经营养因子 由一系列分泌的蛋白质组成，这些蛋白质能引起深刻的 促进发育中的哺乳动物神经系统中神经元的存活。 尽管神经营养因子在神经元存活中的作用是确定无疑的， 神经营养因子支持神经元存活的机制尚不清楚 已澄清。我们建议通过以下方式研究细胞内的信号机制 神经营养因子脑源性神经营养因子(BDNF)促进 发育中大鼠小脑内颗粒神经元的存活。我们最近做了 研究发现，BDNF通过增强小脑颗粒神经元的存活 细胞外调节激酶(ERK)信号通路。ERK激活 激酶，即RSKs，与磷脂酰肌醇-3激酶(PI-3K)-Akt协同作用 信号通路直接抑制凋亡蛋白BAD。此外, 初步数据表明，转录因子肌细胞增强因子 先前参与肌肉发生的2(MEF2)介导BDNF诱导的小脑 颗粒细胞存活。为了阐明转录非依赖性和 BDNF诱导的信号抑制细胞增殖的转录依赖机制 关于细胞死亡机制，我们提出了以下目标：(1)表征 RSK和Akt协同抑制血管内皮细胞生长的机制 凋亡蛋白BAD，(2)表征细胞内信号转导 脑源性神经营养因子诱导MEF-2依赖转录和神经元的途径 生存，以及(3)确定MEF2在人类生存中的作用 器官培养小脑皮质中颗粒神经元的研究 大鼠小脑。总之，拟议中的实验将提供关键的 对神经营养因子细胞内信号机制的洞察 促进哺乳动物中枢神经系统神经元的存活。因为神经营养因子可以 显著保护成熟神经系统中的神经元免受损伤，我们的 调查也应该为小说的发展提供有价值的线索 旨在减轻神经细胞死亡的治疗方法 神经系统包括毁灭性的神经退行性疾病。

DESCRIPTION (From the Applicant's Abstract): The long-term objectives of the proposed research are to elucidate the mechanisms that regulate cell death and survival in the developing mammalian central nervous system. The neurotrophin comprise a family of secreted proteins that elicit the profound effect of promoting survival of neurons in the developing mammalian nervous system. Although the role of neurotrophins in neuronal survival is firmly established, the mechanisms by which neurotrophins support survival of neurons remains to be elucidated. We propose to investigate the intracellular signaling mechanisms by which the neurotrophin brain-derived neurotrophic factor (BDNF) promotes the survival of granule neurons in the developing rat cerebellum. We have recently found that BDNF enhances the survival of cerebellar granule neurons via the extracellular regulated kinase (ERK) signaling pathway. The ERK activates kinases, the Rsks, cooperate with phosphotidylinositol-3 kinase (PI-3K)-Akt signaling pathway to directly inhibit the apoptotic protein BAD. In addition, preliminary data indicate that the transcription factor myocyte enhancer factor 2 (MEF2) previously implicated in myogenesis mediates BDNF-induced cerebellar granule cell survival. To elucidate the transcription-independent and transcription-dependent mechanisms by which BDNF-induced signal suppress the cell death machinery, we propose the following aims: (1) characterize the mechanisms that underlie the cooperativity of Rsk and Akt in suppressing the apoptotic protein BAD, (2) characterize the intracellular signal transduction pathway by which BDNF induced MEF-2 dependent transcription and neuronal survival, and (3) to determine the role that MEF2 plays in the survival of granule neurons in the intact cerebellar cortex in organotypic culture of the rat cerebellum. Together, the proposed experiments will provide critical insights into the intracellular signaling mechanism by which neurotrophin promote the survival of neurons in the mammalian CNS. Since neruotrophins can remarkably protect neurons against injury in the mature nervous system, our investigation should also provide valuable clues for the development of novel therapies aimed at alleviating neuronal cell death occurring in disorders of the nervous system including the devastating neurodegenerative diseases.