MOLECULAR MECHANISMS CONTROLLING PROGRAMMED CELL DEATH

所有的细胞都会死亡。传统上，人们认为细胞死亡是在 衰老或病理。然而，许多正常产生的细胞 在发育过程中被故意诱导死亡。这一过程，众所周知 作为程序性细胞死亡，是正常发育的基础 一种生物体，可以发现相同的细胞组在同一时间死亡 所有个体都处于发育阶段。虽然很多人都知道 对于细胞死亡的时间和空间模式，人们知之甚少 调节这一过程的分子机制。 研究变态蛾和阴性选择的小鼠T细胞， 我们已经克隆了16个不同的基因，它们的表达能力非常强 随着细胞死亡的决定而升高。我们选择了其中的四个 用于详细分析的基因，因为它们在系统发育上是保守的 是调控基因的很好候选者。在这项提案中，我们将 使用遗传、分子和解剖学技术来检验这一假说 这些基因代表了基本的细胞死亡基因。 对介导细胞程序性死亡的基因的理解是 兴趣，因为它代表了一个基本但鲜为人知的 正常动物发育的组成部分。同样，也有很棒的 这些研究可能产生的潜在临床应用。自.以来 所有细胞都携带自杀所需的遗传信息， 以特定于世系的方式操纵这一过程的能力是 显而易见的价值。有可能启动自杀计划 有害细胞，如癌细胞。或者，也有可能 为了阻止原本有价值的细胞的不适当死亡，例如 阿尔茨海默病中的神经元。

All cells die. Traditionally, one thinks of cell death in the context of aging or pathology. However many of the cells that are normally produced during development are intentionally induced to die. This process, known as programmed cell death, is so fundamental to the normal development of an organism, that the same groups of cells can be found to die at the same developmental stage in all individuals. While much is known about the temporal and spatial patterns of cell death, little is known about the molecular mechanisms that mediate this process. Working with metamorphosing moths and negatively selected mouse T cells, we have cloned 16 different genes whose expression is dramatically elevated with the cell's decision to die. We have selected four of these genes for a detailed analysis since they are phylogenetically conserved and are good candidates for regulatory genes. In this proposal, we will use genetic, molecular and anatomical techniques to test the hypothesis that these genes represent essential cell death genes. An understanding of the genes that mediate programmed cell death is of interest because it represents a fundamental but poorly understood component of normal animal development. As well, there are also great potential clinical applications that could arise from these studies. Since all cells carry the genetic information required to commit suicide, the ability to manipulate this process in a lineage-specific manner is of obvious value. It may be possible to activate the suicide program of deleterious cells, such as cancer cells. Alternatively, it may be possible to block the inappropriate death of otherwise valuable cells, such as neurons in Alzheimer's Disease.