SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON SURVIVAL

描述（来自申请人的摘要）： 拟议的研究是阐明调节细胞死亡的机制， 在哺乳动物中枢神经系统发育中的生存。神经营养因子 包括一个分泌蛋白家族， 促进发育中的哺乳动物神经系统中神经元的存活。 虽然神经营养因子在神经元存活中的作用已经确定， 神经营养因子支持神经元存活的机制仍有待进一步研究。 阐明。我们建议研究细胞内的信号机制， 脑源性神经营养因子（BDNF）促进了 发育中大鼠小脑颗粒神经元的存活。我们最近 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，Rsks，与磷脂酰肌醇-3激酶（PI-3K）-Akt 信号通路直接抑制凋亡蛋白BAD。此外，本发明还提供了一种方法， 初步数据表明，转录因子肌细胞增强因子 2（MEF2）先前参与肌发生介导BDNF诱导的小脑 颗粒细胞存活。为了阐明转录独立的， BDNF诱导的信号通过转录依赖性机制抑制 细胞死亡机制，我们提出以下目标：（1）表征 Rsk和Akt在抑制细胞凋亡中的协同作用的基础机制 凋亡蛋白BAD，（2）表征细胞内信号转导 BDNF诱导MEF-2依赖性转录和神经元 生存，以及（3）确定MEF 2在生存中发挥的作用， 小脑皮质颗粒神经元的器官型培养 大鼠小脑总之，拟议的实验将提供关键的 深入了解细胞内信号传导机制， 促进哺乳动物CNS中神经元的存活。由于神经营养素可以 显着保护神经元免受损伤，在成熟的神经系统，我们 调查研究还应为小说的发展提供有价值的线索 目的在于减轻神经元细胞死亡的疗法， 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.