MECHANISM OF PROGRAMMED NEURONAL DEATH

程序性细胞死亡(PCD)是公认的发育现象 这是通过细胞凋亡的过程来实现的。最近的证据有力地表明 PCD在病理情况下也会发生。几行 证据表明，PCD是一种基因表达的结果 特定的遗传程序导致蛋白质杀死细胞。我们有 发现了交感神经中表达增加的几个基因 接受PCD的神经元对剥夺神经营养物质的反应 因子、NGF。我们已经出示证据表明，成员(S)的表达 Fos和Jun转录激活子家族是 神经元性PCD，我们已经鉴定出表达为细胞的新基因 去死吧。此外，我们还发现了一种现象，即总的细胞 核糖核酸，包括绝大多数的信使核糖核酸物种都被很好地降解了。 在细胞被承诺死亡之前。我们提出了多方面的攻击 关于这个问题，要阐明其机理，并最终发挥作用 对神经性PCD的药物控制。 我们将使用各种分子遗传学方法来进一步评估 Fos和Jun家族在神经元性PCD中的作用 建立检测其他潜在感兴趣基因的方法 继续使用差异mRNA显示方法来 鉴定死亡神经元中表达的mRNAs。我们将决定 已经识别的基因以及新识别的基因的作用， 在我们的模型系统中的神经元PCD中。我们将确定这些基因是否 我们已经识别，我们希望识别的那些人，在死亡中表现出来 生死性轴索切断后活体神经元以及这些基因是否 在其他类型的细胞(前列腺上皮、胸腺细胞)中表达 对荷尔蒙信号做出反应而进行PCD。我们将描述 RNAWE显著的、早期的和明显的全球降解现象 在接受PCD的交感神经元中观察到。我们将尝试 确定RNA降解的激活机制及其作用机制 在PCD中的重要性。最后，我们将检查生物化学和遗传学 与小脑颗粒细胞PCD相关的事件。颗粒细胞 系统将允许对我们所拥有的事件的一般性进行评估 在经历PCD的交感神经元中被鉴定，我们希望，并提供 一种具有许多后勤优势的系统，可用于未来的神经元研究 PCD。 这些研究将提供相当大的洞察力来了解 神经元性PCD。鉴于越来越多的证据表明神经元性PCD的作用 在神经系统的病理情况下(中风、神经毒性、 神经退行性疾病)，这些见解可能会导致制定策略 进行药物干预以防止或延缓这些疾病的死亡 条件。

Programmed cell death (PCD) is a well-recognized developmental phenomenon that occurs by a process of apoptosis. Recent evidence strongly suggests that PCD also occurs in pathological conditions. Several lines of evidence have indicated that PCD is the result of the expression of a specific genetic program leading to proteins that kill the cell. We have identified several genes whose expression is increased in sympathetic neurons undergoing PCD in response to deprivation of the neurotrophic factor, NGF. We have presented evidence that expression of member(s) of the Fos and Jun family of transcriptional activators are required for neuronal PCD, and we have identified novel genes expressed as the cells die. In addition we have identified a phenomenon wherein total cellular RNA, including the vast majority of mRNA species, are degraded well before the cell is committed to die. We propose a multi-faceted attack on this problem to elucidate the mechanism of, and ultimately exert pharmacological control over, neuronal PCD. We shall use a variety of molecular genetic approaches to assess further the role of the Fos and Jun family in neuronal PCD, and in doing so establish methods to examine other potential genes of interest We shall continue our use of the differential mRNA display approach to the identification of mRNAs expressed in dying neurons. We shall determine the role of already identified genes, as well as newly identified genes, in neuronal PCD in our model system. We shall determine whether the genes we have identified, and those we hope to identify, are expressed in dying neurons in vivo after death-producing axotomy and whether these genes are expressed in other cell types (prostate epithelium, thymocytes) undergoing PCD in response to hormonal signals. We shall characterize the phenomenon of marked, early, and apparently global degradation of RNA we have observed in sympathetic neurons undergoing PCD. We shall attempt to determine the mechanism of the activation of RNA degradation and its importance in PCD. Finally, we shall examine the biochemical and genetic events associated with PCD of cerebellar granule cells. The granule cell system will allow an assessment of the generality of the events we have identified in sympathetic neurons undergoing PCD, and, we hope, provide a system with many logistical advantages for future study of neuronal PCD. These studies will provide considerable insight into the mechanism of neuronal PCD. Given the increasing evidence for a role of neuronal PCD in pathological conditions of the nervous system (stroke, neurotoxicity, neurodegenerative disease), these insights may lead to strategies to intervene pharmacologically to prevent or retard death in these conditions.