NEUROTROPHIC FACTOR DEPRIVATION AND NEURONAL CELL DEATH

神经营养因子剥夺和神经元细胞死亡

• 批准号: 2272635
• 负责人: LLOYD A GREENE
• 金额: $ 19.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-01 至 1997-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2272635
• 关键词: DNA; PC12 cells; acetylcysteine; antioxidants; apoptosis; cyclins; glutathione; growth inhibitors; laboratory mouse; laboratory rat; neural degeneration; neuroprotectants; neurotrophic factors; protein kinase; sympathetic nervous system; tissue /cell culture

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.

该项目的长期目标是揭示分子 营养因子支持神经元存活的机制 当失去营养支持时哪些神经元会发生凋亡 特别是，我们将测试假设（由最近的工作提出） 来自我们自己和其他实验室的）：a）神经元经历细胞凋亡 当它们不恰当地尝试重新进入细胞周期时死亡； b) NGF 等营养因子通过阻止神经元接触来促进存活 细胞周期； c) 营养因子的撤回导致神经元 尝试重新进入细胞周期，但它们以不适当的方式这样做 协调方式并经历凋亡性死亡。对这些假设的检验 将使用大鼠 Pc12 嗜铬细胞瘤细胞培养物进行 啮齿动物的交感神经元需要神经生长因子（NGF） 他们的营养支持。具体目标包括：（1）．研究机制 N-乙酰半胱氨酸可挽救神经元细胞免于凋亡 由于营养支持的取消而引起。特别是，要确定 这种药物的促进生存作用是否是由于其直接作用 抗氧化特性或间接增强其能力 细胞内谷胱甘肽的水平，以及是否（正如我们所相信的）它 促进生存的行为是由于它的能力（最近发现 由我们）阻止细胞增殖。 （2）。判断是否 阻止神经元细胞的操作（药理学和分子） 进入或重新进入细胞周期（特别是从 进入S期），将防止其引起的凋亡性死亡 撤回营养支持。这将部分完成 干扰特定 G0-G1 期的表达和/或活性 调节分子，包括细胞周期蛋白和细胞周期蛋白依赖性激酶 （CDK）。 （3）。确定营养因子和其他物质是否 通过对神经元的特定作用来预防神经细胞凋亡 细胞周期和参与调节细胞的特定分子 循环。我们坚信，对 营养因子防止神经元死亡的机制以及 当失去营养支持时，神经元就会死亡 开发合适的药物疗法来预防或改善 神经退行性疾病。如果可以的话，情况尤其如此 建立细胞周期相关分子参与治理 神经元的生与死。