Molecular Pathways In Apoptosis And Viral Cytopathicity

很明显，体内的死亡程序控制着体内细胞的数量和类型。疾病可能是由于细胞死亡效率低下或不适当或过度死亡造成的，例如艾滋病期间由人类免疫缺陷病毒（艾滋病毒）造成的死亡。在这个项目中，我们正在采取多方面的方法来研究这种死亡程序在淋巴细胞以及其他细胞类型中的分子机制。我们研究的主要焦点是一种叫做CD95/Fas/APO-1的细胞表面受体，它在刺激细胞死亡中起着重要作用，主要是在免疫系统中。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。我们特别关注了一种被称为Flice/Mach1 （caspase-8）的蛋白酶的激活，它可以直接执行死亡程序。我们已经描述了两种来自Fas受体的死亡程序，一种是caspase-8依赖的，另一种是caspase-8独立的。这两种形式的淋巴细胞死亡的调控和分子途径是不同的。此外，我们还发现了一个主要的细胞死亡程序，显示出特殊的细胞质膜结构，称为自噬，这是由抑制caspase-8引发的。这些研究将帮助我们确定细胞如何启动它们自己的死亡。我们正在探索这一事件的调控如何在各种疾病中发挥作用，从自身免疫性疾病到艾滋病、SARS和分枝杆菌感染等传染病。特别是，在感染艾滋病毒后，艾滋病发病的一个关键影响被认为是由病毒引起的T淋巴细胞死亡。我们已经发现这种死亡过程不同于细胞凋亡，并且在鉴定参与这一过程的病毒基因产物方面正在取得进展。然后，我们将从生化角度解释病毒产物是如何触发T细胞死亡的。

It has become clear that an internal death program controls the number and types of cells in the body. Diseases can result from inefficient cell 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 as well as other cell types. 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. In addition, we have discovered a major program of cell death exhibiting particular cytoplasmic membrane structures called autophagy which is triggered by the inhibition of caspase-8. These studies will help us to determine how cells can initiate their own death. We are exploring how the regulation of this event may play a role in various diseases ranging from autoimmune conditions to infectious diseases such as AIDS, SARS, and mycobacterial infections. In particular, 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.