NEUROTROPHIC FACTOR DEPRIVATION AND NEURONAL CELL DEATH

这个项目的长期目标是揭示 营养因子支持神经元存活的机制， 神经元在失去营养支持后会发生凋亡 特别是，我们将测试的假设（建议由最近的工作 从我们自己的和其他实验室）：a）神经元经历凋亡 当它们不适当地试图重新进入细胞周期时死亡; B） 营养因子，如神经生长因子，通过使神经元不受损伤来促进存活。 细胞周期; c）营养因子的撤回导致神经元 试图重新进入细胞周期，但他们这样做是在一个不适当的 协调的方式并经历凋亡性死亡。对这些假设的检验 将使用大鼠Pc 12嗜铬细胞瘤细胞的培养物进行， 啮齿动物交感神经元需要神经生长因子（NGF）， 营养支持。具体目标包括：（1）。可能机制 N-乙酰半胱氨酸通过其拯救神经元细胞免于凋亡性死亡 是由营养支持的撤销引起的。特别是，确定 这种药物的生存促进作用是否是由于其直接的， 抗氧化特性或其间接增加 谷胱甘肽的细胞内水平，以及是否（正如我们所认为的）其 生存促进行动是由于它的能力（最近发现， 通过我们）来阻断细胞增殖。 （二）、以确定是否 操作（药理学和分子），防止神经细胞 进入或重新进入细胞周期（特别是， 进入S期），将阻止它们的凋亡性死亡， 停止营养支持。这将部分通过以下方式实现： 干扰特异性G 0-G1期的表达和/或活性 包括细胞周期蛋白和细胞周期蛋白依赖性激酶的调节分子 （Cdks）.（三）、为了确定是否营养因子和其他因子， 防止神经元凋亡性死亡是通过对 细胞周期和参与调节细胞周期的特定分子 周期我们坚信， 营养因子防止神经元死亡的机制， 神经元死亡时，剥夺营养支持将提供手段和 开发合适的药物治疗以预防或改善 神经退行性疾病尤其是如果一个人能够 建立参与细胞周期相关分子在治理 神经元的生命和死亡

The long-term goals of this project are to uncover the molecular mechanisms by which trophic factors support neuronal survival and by which neurons undergo apoptotic death when deprived of trophic support In particular, we shall test the hypotheses (suggested by recent work from our own and other laboratories) that: a) Neurons undergo apoptotic death when they inappropriately attempt to reenter the cell cycle; b) Trophic factors such as NGF promote survival by keeping neurons out of the cell cycle; c) Withdrawal of trophic factors causes neurons to attempt to re-enter the cell cycle, but they do so in an inappropriately coordinated manner and undergo apoptotic death. Tests of these hypotheses will be carried out using cultures of rat Pc12 pheochromocytoma cells and rodent sympathetic neurons that require nerve growth factor (NGF) for their trophic support. Specific aims include: (1). To study the mechanism by which N-acetylcysteine rescues neuronal cells from apoptotic death caused by withdrawal of trophic support. In particular, to determine whether the survival-promoting actions of this drug are due to its direct anti-oxidative properties or to its indirect ability to increase intracellular levels of glutathione, and whether (as we believe) its survival-promoting actions are due to its ability (recently discovered by us) to block cellular proliferation. (2). To determine whether manipulations (pharmacological and molecular) that prevent neuronal cells from entering or re-entering the cell cycle (and in particular, from entering S phase), will prevent their apoptotic death caused by withdrawal of trophic support. This will be accomplished in part by interfering with the expression and/or activity of specific G0-G1 phase regulatory molecules including cyclins and cyclin-dependent kinases (Cdks). (3). To determine whether trophic factors and other agents that prevent neuronal apoptotic death do so by means of specific effects on cell cycle and on specific molecules that are involved in regulating cell cycle. We are of the conviction that a clear understanding of the mechanism(s) by which trophic factors prevent neuronal death and by which neurons perish when deprived of trophic support will provide mean& to develop suitable pharmacologic therapies to prevent or ameliorate neurodegenerative conditions. This will be especially so if one can establish involvement of cell cycle-related molecules in governance of neuronal life and death.