MITOCHONDRIAL FUNCTION IN APOPTOSIS

描述(逐字摘自研究人员摘要)：细胞凋亡是一种 一种主动的细胞自杀形式，确保多余或不受欢迎的 细胞就被消灭了。除了在胚胎发育和生理学上的重要性外， 这一现象在该病的病因和治疗中具有重要意义。 癌症、艾滋病和阿尔茨海默氏症等疾病。细胞内 细胞凋亡的途径还不完全清楚。然而，基本的机械是 在物种和细胞类型中很大程度上保守。我们一直在研究 基于卵子提取物的无细胞系统的细胞凋亡机制研究 青蛙，非洲爪哇。该系统显示真实的生化和 细胞凋亡的形态特征，并已被用于揭示新的方面 在细胞凋亡过程中，尤其是Bcl2在阻断细胞周期中的作用 从线粒体释放细胞色素c，从而阻止caspase 激活和凋亡。最近的研究表明，某些促凋亡剂 包括Bax和Bid在内的Bcl2的亲属可以直接与 线粒体导致细胞色素c的释放。这项研究在这里提出 旨在确定BID和BAX导致外部 线粒体膜对细胞色素c等蛋白质具有通透性。首先，我们 将决定Bax和Bid诱导的细胞色素c的释放是否会发生 而不会损害线粒体功能的其他方面，特别是 通过经典途径输入蛋白质。第二，我们将阐明 Bax和Bid诱导膜的分子机制 渗透化，使用从孤立的整体到复杂程度不等的系统 线粒体到合成脂质体，再用纯化的或 重组蛋白。最后，我们将使用生化和遗传方法来 确定介导或调节线粒体事件的新蛋白质 依赖于BAX或BID的通路。这些研究将有助于解决以下问题 细胞凋亡程序中的线粒体事件是否代表NO点 返回，或者在某些条件下可以反转，导致单元格 生死存亡。

DESCRIPTION (appended verbatim from investigator's abstract): Apoptosis is an active form of cellular suicide that ensures that superfluous or undesirable cells are eliminated. Besides its importance in embryogenesis and physiology, this phenomenon has considerable significance in the etiology and treatment of disorders such as cancer, AIDS and Alzheimer's Disease. The intracellular pathways of apoptosis are not fully understood. However, the basic machinery is largely conserved among species and cell types. We have been studying the mechanisms of apoptosis using a cell-free system based on extracts from eggs of the frog, Xenopus laevis. This system displays authentic biochemical and morphological features of apoptosis, and has been used to uncover novel aspects of the apoptotic process, particularly the function of Bcl-2 in blocking the release of cytochrome c from mitochondria, thereby preventing caspase activation and apoptosis. Recent studies have shown that certain pro-apoptotic relatives of Bcl-2, including Bax and Bid, can interact directly with mitochondria to cause the release of cytochrome c. The research proposed here aims to determine the mechanisms through which Bid and Bax cause the outer mitochondrial membrane to be permeable to proteins like cytochrome c. First, we will determine whether Bax- and Bid-induced cytochrome c release can occur without compromising other aspects of mitochondrial function, particularly protein import via the classical pathway. Second, we will elucidate the molecular mechanisms through which Bax and Bid induce membrane permeabilization, using systems that range in complexity from isolated whole mitochondria down to synthetic liposomes reconstituted with purified or recombinant proteins. Finally, we will use biochemical and genetic methods to identify novel proteins that mediate or modulate the mitochondrial events in Bax- or Bid-dependent pathways. Such studies will help address the question of whether mitochondrial events in the apoptotic program represent a point of no return, or instead can be reversed under certain conditions, resulting in cell survival.