Molecular Pathways--Programmed Death/Viral Cytopathicity

内部死亡程序控制体内细胞的数量和类型。疾病可能是由于无效的细胞死亡或不适当或过度的死亡，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以及其他细胞类型的凋亡和非凋亡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，它在刺激主要在免疫系统中的细胞凋亡和非凋亡性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。此外，我们还发现了一个主要的细胞死亡程序，它表现出被称为自噬的特定细胞质膜结构，这是由caspase-8的抑制引发的。我们已经发现，自噬性死亡程序是由于过氧化氢酶的选择性降解，导致活性氧的显着过度积累和随之而来的细胞损伤。这些研究将帮助我们确定细胞如何启动自己的死亡。我们正在探索如何调节这一事件可能在各种疾病中发挥作用，从自身免疫性疾病到感染性疾病，如艾滋病，SARS和分枝杆菌感染。特别是，在感染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。为了严格地研究这一过程，我们构建了一个数学模型来分析HIV感染期间组织培养中的细胞死亡。在未来，我们希望解释病毒产物如何在生化方面触发T细胞的死亡。在非淋巴细胞的SARS感染中，我们已经确定了引起非凋亡性死亡的病毒成分，并正在研究诱导死亡的模式。

Internal death programs control 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 both apoptotic and nonapoptotic death programs 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 both apoptotic and nonapoptotic 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. We have discovered that the autophagic death program is due to the selective degradation of catalase which leads to a marked overaccumulation of reactive oxygen species and consequent cellular damage. 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. in order to study this process rigorously we have constructed a mathematical model to analyze cell death in tissue culture during HIV infection. In the future, we would like to explain how the viral products triggers the death of T cells in biochemical terms. In SARS infections of nonlymphoid cells, we have identified viral components that cause nonapoptotic death and are studying the mode of death induced.