Analysis of FADD-dependent regulation of programmed cell death

在人体内，许多不同类型的细胞都具有自我毁灭（即自杀）的能力。现在广泛认识到几种不同形式的细胞自杀（凋亡，坏死性凋亡，自噬以及内部变体）。这些自我导向或“程序化”的死亡形式与其他形式的细胞破坏相反，例如坏死（直接细胞衰变）或吞噬作用，其中其他细胞类型共同杀死靶标。 程序性细胞死亡或PCD在防止异常细胞的积累和生长中起着关键作用。 PCD还起到防止其他正常细胞群过度积累的作用。正因为如此，PCD过程对于所有多细胞生物体的正常发育和维持都是绝对必要的。关于调节PCD信号传导的蛋白质-蛋白质相互作用，已经表征了两个主要途径。这些信号系统被称为“内在”和“外在”途径，它们控制给定细胞如何对PCD方面的各种潜在破坏性刺激做出反应。在外在途径中，特征蛋白（配体）与位于细胞膜上的特定“死亡受体”的结合促进PCD的诱导。我们实验室和其他实验室最近的工作表明，死亡受体结合诱导几种形式的细胞通讯，特别是凋亡，程序性坏死，和/或NFkB信号传导，这取决于信号传导的背景。然而，关于启动、协调和控制这些进程的确切机制的细节尚不清楚。目前的建议检查这些功能活动是如何在蛋白质复合物内协调的，该蛋白质复合物结合死亡受体并启动信号传导（称为DISC）。 具体而言，这些研究检查了死亡受体激活后招募到DISC的蛋白质的翻译后修饰。特别感兴趣的是caspase-8在这个过程中的作用，以及如何修改这些蛋白质的相互作用，以改变细胞凋亡与坏死性凋亡（两种不同形式的PCD）之间的平衡，在遗传修饰的原代细胞为基础的系统暴露于PCD刺激。

In the human body, many different cell types possess the ability to destroy themselves (i.e. commit suicide). Several different forms of cell suicide are now widely recognized (apoptosis, necroptosis, autophagy, as well as internal variants). These self-directed or "programmed" forms of death operate in contrast to other forms of cellular destruction such as necrosis (direct cellular decay) or phagocytosis in which additional cell types conspire to kill the target. Programmed cell death or PCD plays a critical role in preventing the accumulation and growth of abnormal cells. PCD also acts to prevent the excessive accumulation of otherwise normal cellular populations. Because of this, the process of PCD is absolutely required for both normal development and the maintenance of all multi-cellular organisms. With respect to the protein-protein interactions which regulate PCD signaling two major pathways have been characterized. Termed the "intrinsic" and "extrinsic" pathways, these signaling systems control how a given cell will respond to a wide array of potentially damaging stimuli in terms of PCD. In the extrinsic pathway, binding of characteristic proteins (ligands) to specific "death receptors" located on the cell membrane promotes the induction of PCD. Recent work from our laboratory and others has shown that death receptor binding induces several forms of cell communication, specifically apoptosis, programmed necrosis, and/or NFkB signaling depending upon the signaling context. However details concerning the precise mechanisms by which these processes are initiated, coordinated and controlled is unclear. The current proposal examines how these functional activities are coordinated within the protein complex which binds to the death receptor and initiates signaling (termed the DISC). Specifically these studies examine the post-translational modification of proteins which are recruited to the DISC following death receptor activation. Of particular interest is the role of caspase-8 in this process, and how modification of these protein interactions may act to alter the balance between apoptosis versus necroptosis (two distinct forms of PCD) in genetically modified primary cell-based systems following exposure to PCD stimuli.