MITOCHONDRIAL FUNCTION IN APOPTOSIS

描述（从研究者摘要中逐字附上）：细胞凋亡是一种 细胞自杀的活性形式，确保多余的或不需要的 细胞被消灭。除了在胚胎发生和生理学上的重要性外， 这一现象在疾病的病因学和治疗方面具有相当重要的意义。 癌症、艾滋病和阿尔茨海默病等疾病。细胞内 细胞凋亡的途径尚未完全了解。然而，基本的机器是 在物种和细胞类型中大部分是保守的。我们一直在研究 细胞凋亡的机制，使用无细胞系统的基础上提取的鸡蛋， 非洲爪蟾该系统显示真实的生化和 细胞凋亡的形态学特征，并已被用来揭示新的方面 凋亡过程，特别是Bcl-2在阻断细胞凋亡中的作用， 从线粒体释放细胞色素c，从而阻止半胱天冬酶 激活和凋亡。最近的研究表明，某些促细胞凋亡 Bcl-2的亲属，包括Bax和Bid，可以直接与 线粒体引起细胞色素c的释放。这里提出的研究 目的是确定通过出价和Bax引起外部的机制， 线粒体膜可渗透细胞色素c等蛋白质。一是 将确定Bax和Bid诱导的细胞色素c释放是否会发生 而不损害线粒体功能的其他方面， 通过经典途径输入蛋白质。第二，我们将阐明 Bax和Bid诱导细胞膜凋亡的分子机制 渗透化，使用从孤立的整体复杂的系统， 线粒体下降到用纯化的或 重组蛋白最后，我们将使用生物化学和遗传学方法， 鉴定介导或调节线粒体事件的新蛋白质， Bax或Bid依赖性通路。这些研究将有助于解决以下问题： 凋亡程序中的线粒体事件是否代表了一个点， 返回，或者相反，在某些条件下可以反转，导致单元格 生存

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.