Molecular Pathways In Apoptosis And Viral Cytopathicity

很明显，内部死亡程序控制着体内免疫细胞的数量和类型。疾病可以由淋巴细胞的无效死亡或由不适当或过度的死亡引起，例如艾滋病期间由人类免疫缺陷病毒（HIV）引起的死亡。在这个项目中，我们正在采取多方面的方法来研究淋巴细胞中这种死亡程序的分子机制。我们研究的一个主要焦点是一种称为CD 95/Fas/APO-1的细胞表面受体，它在刺激免疫系统细胞死亡中起着重要作用。我们正试图了解这种受体是如何刺激细胞内机制导致细胞死亡的。特别是，我们专注于一种名为Flice/Mach 1（半胱天冬酶-8）的蛋白酶的激活，它可以直接执行死亡程序。我们的特点是两个死亡程序，来自Fas受体，一个是caspase-8依赖性和其他caspase-8独立。这两种形式的淋巴细胞死亡的调节和分子途径是不同的。这些研究将帮助我们确定细胞如何启动自己的死亡。该事件的调节可能在从自身免疫性疾病到感染性疾病如艾滋病的各种疾病中发挥作用。感染HIV后，艾滋病发病的关键作用被认为是由病毒引起的T淋巴细胞死亡。我们发现这种死亡过程与细胞凋亡不同，并且在鉴定参与该过程的病毒基因产物方面取得了进展。然后，我们想解释病毒产物如何在生物化学方面触发T细胞的死亡。

It has become clear that an internal death program controls the number and types of immune cells in the body. Diseases can result from inefficient lymphocyte death or from inappropriate or excessive death such as is caused by the human immunodeficiency virus (HIV) during AIDS. In this project we are taking a multifaceted approach to studying molecular mechanisms of this death program in lymphocytes. A major focus of our investigations is a cell surface receptor called CD95/Fas/APO-1 that plays an important role in stimulating the death of cells mainly in the immune system. We are trying to understand how this receptor stimulates the intracellular machinery that causes cellular demise. In particular we have focused on the activation of a protease termed Flice/Mach1 (caspase-8) which can directly carry out the death program. We have characterized two death programs that emanate from the Fas receptor, one which is caspase-8 dependent and the other which is caspase-8 independent. The regulation and molecular pathways of these two forms of lymphocyte death are distinct. These studies will help us to determine how cells can initiate their own death. The regulation of this event may play a role in various diseases ranging from autoimmune conditions to infectious diseases such as AIDS. Following infection with HIV, a critical effect in the onset of AIDS is believed to be death of T lymphocytes caused by the virus. We have found that this death process is distinct from apoptosis and are making progress in indentifying the viral gene product(s)that are involved in this process. We would then like to explain how the virus product triggers the death of T cells in biochemical terms.