MECHANISM OF PROGRAMMED NEURONAL DEATH

细胞程序性死亡是一种公认的发育现象 这是通过细胞凋亡过程发生的。 最近的证据有力地表明 PCD也会在病理状态下发生。几行 有证据表明，PCD是一个表达的结果， 特定的遗传程序导致杀死细胞的蛋白质。我们有 发现了几个基因，其表达在交感神经系统中增加， 经历PCD的神经元对神经营养素剥夺的反应 因子，NGF。我们已经提出证据表明，表达成员（S）的 转录激活因子Fos和Jun家族是 神经元PCD，我们已经确定了新的基因表达的细胞 死的此外，我们还发现了一种现象， RNA，包括绝大多数mRNA种类， 在细胞死亡之前。我们建议采取多方面的攻击 在这个问题上阐明的机制，并最终发挥 药理学控制，神经元PCD。 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PCD中的作用， 建立检测其他潜在的感兴趣基因的方法 我们继续使用差异mRNA显示方法， 鉴定垂死神经元中表达的mRNA。我们将决定 已经发现的基因，以及新发现的基因， 在我们的模型系统中的神经元PCD。我们将确定基因是否 我们已经确定的，以及我们希望确定的，都是在死亡中表达的。 神经元在体内死亡后产生轴突切断术，以及这些基因是否 在其他细胞类型（前列腺上皮、胸腺细胞）中表达 在荷尔蒙信号的作用下经历PCD我们将描述 RNA的显著、早期和明显的全局降解现象， 在经历PCD的交感神经元中观察到。我们将试图 确定RNA降解的激活机制及其 PCD的重要性。最后，我们将研究生物化学和遗传学。 与小脑颗粒细胞PCD相关的事件。颗粒细胞 系统将允许我们对事件的一般性进行评估， 在经历PCD的交感神经元中发现，我们希望， 一个具有许多后勤优势的系统，用于未来的神经元研究 PCD。 这些研究将提供相当深入的机制， 神经元PCD鉴于越来越多的证据表明神经元PCD的作用 在神经系统的病理状态（中风，神经毒性， 神经退行性疾病），这些见解可能会导致策略， 进行干预，以防止或延缓这些 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.