Signal integration of the death receptor pathways

生物系统在许多意义上是复杂的，特别是涉及到多个途径。 在启动和调节病理生理过程中。我们感兴趣的是不同的信号事件 可以与对这些过程至关重要的细胞死亡机制相互作用。在早期的研究中，我们定义了 促死亡蛋白Bid在死亡受体途径和细胞周期调控中的关键作用 小鼠肝损伤和肝细胞凋亡模型中的线粒体途径。从那时起，我们就 研究发现，新的信号事件参与了这些通路，特别是当肿瘤坏死因子-R1参与的时候。基座 在我们的初步研究中，我们假设JNK和ROS是两个重要的 可以独立于BID与线粒体激活整合的机制。我们将解决 JNK在促进TNFa诱导的肝细胞凋亡和肝损伤中的作用(目标1)及JNK如何 以一种与投标无关的方式激活线粒体(目标2)。在目标3中，我们将研究ROS在 肿瘤坏死因子α诱导的肝损伤和肝细胞凋亡，核因子-KB途径对其的调节及其可能的机制 以一种与投标无关的方式激活线粒体。将采取各种方法，包括在 利用基因敲除小鼠和RNAi体内基因敲除的活体模型，体外原代细胞 培养和生化分析。虽然这项提案的重点是整合一些关键的 在TNFa刺激后线粒体水平的信号传递过程，我们的长期目标是了解 如何整合不同的信号通路以确定病理过程的最终结果， 这对新疗法的发展将是重要的。

The biology system is complicated in many senses, in particular regarding to the multiple pathways involved in initiating and regulating pathophysiological processes. We are interested in how different signaling events could interact with the cell death machinery important to these processes. In earlier studies, we defined the critical role of Bid, a pro-death Bcl-2 family protein, in the cross-talk between the death receptor pathway and the mitochondria pathway in a murine model of liver injury and hepatocyte apoptosis. We have since then found that novel signaling events are involved in the pathways, particularly when TNF-R1 is engaged. Based on our preliminary studies, we hypothesize that JNK and reactive oxygen species (ROS) are two important mechanisms that could integrate with the mitochondrial activation independently of Bid. We will address the function of JNK in promoting TNFa-induced hepatocyte apoptosis and liver injury (Aim 1) and how JNK may activate the mitochondria in a Bid-independent way (Aim 2). In Aim 3, we will investigate the role of ROS in TNFa induced liver injury and hepatocyte apoptosis, their regulation by the NF-KB pathway and how they may activate the mitochondria in a Bid-independent manner. A variety of approaches will be taken, including the in vivo models that utilize gene knockout mice and in vivo gene knockdown by RNAi, in vitro primary cell cultures and biochemistry analysis. While the focus of this proposal is at the integration of some of the key signaling processes at the mitochondria level following TNFa stimulation, our long-term goal is to understand how different signal pathways can be integrated to determine the final outcome of a pathological process, which would be important to the development of novel therapeutics.