Modulation of Acute Liver Injury

这项研究的目的是确定在肝细胞凋亡中调节肝细胞死亡的细胞信号。 对中毒性肝损伤的反应。我们的一般假设是，细胞死亡不仅仅是一种被动的 由毒素的生化作用引起的过程，而是由细胞信号主动调节的过程 基因和蛋白质表达的级联和变化。肝细胞对毒性损伤反应的关键 是由肿瘤坏死因子-α（TNF）和活性氧（ROS）激活的死亡途径。 在上一个资助期完成的研究已经确定了c-Jun N-末端激酶（JNK）/c-Jun N-末端激酶（JNK）。 Jun/AP-1信号通路作为TNF和ROS引起的肝细胞死亡的中心调节因子初步 数据已经证明了不同JNK同种型在这些细胞中独特的促凋亡和促存活作用。 肝细胞死亡的两种形式根据这些研究和其他初步数据，我们提出 核心假设是肝细胞对毒性损伤的存活或死亡取决于 由不同JNK差异调节的促凋亡和抗凋亡信号的整合 同种型。我们将通过描述不同JNK亚型的具体功能来验证这一假设。 培养的肝细胞和肝毒性损伤的体内模型中的研究包含在四个具体目标。 首先，我们将检验JNK过度激活使肝细胞对TNF引起的凋亡敏感的假设， 诱导E3连接酶介导的C/EBP β降解。其次，我们将检验毒素 通过JNK 2诱导的线粒体死亡途径的激活使肝脏对TNF的损伤敏感。 第三，我们将检验JNK 1和JNK 2对氧化诱导的细胞凋亡具有相反作用的假设。 肝细胞死亡通过他们的差异调节磷酸-c-六月。第四，我们将测试的假设 促凋亡Bcl-2家族成员Bim是c-Jun调节的肝细胞下游效应子， 死于氧化应激这些研究的最终目标是进一步了解 肝细胞死亡的机制，并促进治疗的发展，以防止肝衰竭。 与公共卫生的相关性：每种类型的肝病的最终问题是肝脏的损伤和死亡。 肝细胞，导致肝功能丧失和肝功能衰竭。了解的机制 肝细胞死亡对于预防肝病引起的肝衰竭是至关重要的。

The objective of the proposed studies is to identify the cellular signals that regulate hepatocyte death in reponse to toxic liver injury. Our general hypothesis has been that cell death is not merely a passive process resulting from the biochemical effects of toxins but rather is actively regulated by cellular signaling cascades and changes in gene and protein expression. Critical to the hepatocyte's reponse to toxic injury are the death pathways activated by tumor necrosis factor-a (TNF) and reactive oxygen species (ROS). Studies completed over the last funding period have identified the c-Jun N-terminal kinase (JNK)/c- Jun/AP-1 signaling pathway as a central regulator of hepatocyte death from TNF and ROS. Preliminary data have demonstrated unique pro-apoptotic and pro-survival effects of different JNK isoforms in these two forms of hepatocyte death. Based on these studies and other preliminary data we propose the central hypothesis that hepatocyte survival or death in response to toxic injury is dictated by the integration of pro- and anti-apoptotic signals that are differentially regulated by distinct JNK isoforms. We will test this hypothesis by delineating the specific functions of different JNK isoforms in cultured hepatocyte and in vivo models of hepatotoxic injury in studies contained in four Specific Aims. First, we will test the hypothesis that JNK overactivation sensitizes hepatocytes to apoptosis from TNF by inducing E3 ligase-mediated degradation of C/EBPp. Second, we will test the hypothesis that toxins sensitize the liver to injury from TNF through JNK2-induced activation of the mitochondrial death pathway. Third, we will test the hypothesis that JNK1 and JNK2 have opposing effects on oxidant-induced hepatocyte death through their differential regulation of phospho-c-Jun. Fourth, we will test the hypothesis that the pro-apoptotic Bcl-2 family member Bim is the c-Jun-regulated downstream effector of hepatocyte death from oxidative stress. The ultimate goal of these studies is to further our understanding of the mechanisms of hepatocyte death and facilitate the development of therapies to prevent hepatic failure. Relevance to public health: The ultimate problem in every type of liver disease is the injury and death of hepatocytes that leads to the loss of hepatic function and liver failure. Understanding the mechanisms of hepatocyte death is critical to the prevention of hepatic failure from liver disease.