Molecular Pathways In Apoptosis And Viral Cytopathicity

很明显，体内死亡程序控制着体内细胞的数量和类型。疾病可由低效的细胞死亡或不适当或过度的死亡引起，如艾滋病期间人类免疫缺陷病毒(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淋巴细胞和其他细胞类型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CD95/Fas/APO-1的细胞表面受体，它在刺激细胞死亡方面发挥着重要作用，主要是在免疫系统中。我们正试图了解这种受体如何刺激导致细胞死亡的细胞内机制。特别是，我们重点研究了一种名为Flice/Mach1(caspase-8)的蛋白酶的激活，它可以直接执行死亡程序。我们已经确定了两个源于Fas受体的死亡程序，一个依赖于caspase-8，另一个不依赖于caspase-8。这两种形式的淋巴细胞死亡的调节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，表现出特殊的细胞质膜结构，称为自噬，它是由抑制caspase-8触发的。这些研究将帮助我们确定细胞如何启动自己的死亡。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，从自身免疫疾病到传染病，如艾滋病、SARS和分枝杆菌感染。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病毒导致的T淋巴细胞死亡。我们发现这一死亡过程不同于细胞凋亡，并在识别参与这一过程的病毒基因产物(S)方面取得了进展。然后我们想从生物化学的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.