ALCOHOL AND THE CONTROL OF LIVER REGENERATION

描述（改编自申请人的摘要）：肝再生是一种治疗肝再生的方法。 对正常静止的肝细胞重新进入的损伤的独特修复反应 细胞周期并进行细胞分裂，恢复受损或丢失的组织， 同时维持细胞的分化功能。急性或慢性 乙醇治疗损害肝再生的机制仍然很差， 表征了肝脏正常修复功能的失调可能 导致酒精性肝病的发展。长期 这些研究的目的是表征细胞内信号传导事件 与肝再生相关，并评估这些信号过程 受到慢性酒精治疗的影响。生长因子发挥着重要的 在肝再生过程中的作用。肝再生的开始 （引发）与生长因子受体的激活有关， 它们的下游信号通路我们的第一个具体目标是描述 大鼠表皮生长因子受体信号通路激活 部分肝切除术后和用肿瘤预处理肝脏后的肝脏 坏死因子-α或其他治疗。我们将决定如何 引发诱导的生长因子反应模式的激活受到以下因素的影响： 慢性酒精治疗第二个具体目标侧重于以下方面的作用： 细胞凋亡在生长因子反应的激活中的作用。的早期阶段 肝再生可能依赖于肝细胞凋亡过程的激活， 肝细胞因子和适当的细胞防御这些凋亡 信号.线粒体是这些信号的关键靶点。慢性乙醇 治疗影响线粒体功能，并促进其对 促凋亡信号。我们将研究如何平衡亲和 抗凋亡因子在肝硬化发病期间影响线粒体功能 再生以及这种平衡如何受到慢性乙醇处理的影响。的 第三个具体目标是解决线粒体在能量应激相关的作用， 部分肝切除术后肝再生。 我们假设增强的 能量需求激活细胞内信号传导过程，导致细胞内 线粒体代谢和增强的氧化应激。慢性乙醇治疗 减少线粒体对增加的能量需求作出反应的能力 增加氧化应激。我们将研究慢性乙醇治疗如何影响 部分肝切除术后肝脏的能量状态，导致信号缺陷 肝再生所需的蛋白质

DESCRIPTION (Adapted from the Applicant's Abstract): Liver regeneration is a unique repair response to damage where normally quiescent liver cells reenter the cell cycle and undergo cell division, regaining the damaged or lost tissue, while maintaining the differentiated function of the cells. Acute or chronic ethanol treatment impairs liver regeneration by mechanisms that remain poorly characterized. Deregulation of the liver's normal repair function may contribute to the development of alcoholic liver disease. The long-term objective of these studies is to characterize intracellular signaling events associated with liver regeneration and to assess how these signaling processes are affected by chronic ethanol treatment. Growth factors play an important role in the progression of liver regeneration. The onset of liver regeneration (priming) is associated with an activation of the growth factor receptors and their downstream signaling pathways. Our first specific aim is to characterize the activation of epidermal growth factor receptor signaling pathways in rat liver after partial hepatectomy and after priming of the liver with tumor necrosis factor-alpha or other treatments. We will determine how the priming-induced activation of growth factor response patterns is affected by chronic ethanol treatment. The second specific aim focuses on the role of apoptosis in the activation of growth factor responses. The early phase of liver regeneration may depend on the activation of apoptotic processes in the liver by cytokines and the appropriate cellular defense against these apoptotic signals. Mitochondria are a critical target for these signals. Chronic ethanol treatment affects mitochondrial function and promotes their susceptibility to pro-apoptotic signals. We will investigate how the balance of pro- and anti-apoptotic factors affects mitochondrial function during the onset of liver regeneration and how this balance is affected by chronic ethanol treatment. The third specific aim addresses the role of mitochondria in the energy stress associated with liver regeneration after partial hepatectomy. We presume that the enhanced energy demand activates intracellular signaling processes, resulting in changes in mitochondrial metabolism and enhanced oxidative stress. Chronic ethanol treatment diminishes the capacity of the mitochondria to respond to increased energy demand and increases oxidative stress. We will study how chronic ethanol treatment affects the energy state of the liver after partial hepatectomy, resulting in defects in the signals that are required for the onset of liver regeneration.