ALCOHOL AND THE CONTROL OF LIVER REGENERATION

描述(改编自申请者摘要)：肝脏再生是一种 对正常静止的肝细胞重新进入的损伤做出独特的修复反应 细胞循环并经历细胞分裂，重新获得受损或丢失的组织， 同时维持细胞的分化功能。急性或慢性 乙醇治疗通过仍然不佳的机制损害肝脏再生 特色化的。解除对肝脏正常修复功能的管制可能会 促进酒精性肝病的发展。长期的 这些研究的目的是表征细胞内信号事件 与肝脏再生相关，并评估这些信号过程如何 都会受到慢性乙醇治疗的影响。增长因素发挥着重要的作用 在肝脏再生过程中的作用。肝再生的开始 (启动)与生长因子受体的激活和 它们的下游信号通路。我们的第一个具体目标是 大鼠表皮生长因子受体信号通路的激活 肝部分切除和肿瘤肝脏预充后的肝脏 肿瘤坏死因子-α或其他治疗。我们将决定如何 启动诱导生长因子反应模式的激活受以下因素的影响 慢性乙醇治疗。第二个具体目标侧重于 细胞凋亡在激活生长因子反应中的作用。的早期阶段 肝再生可能依赖于肝细胞凋亡过程的激活。 细胞因子在肝脏中的作用及其对细胞凋亡的适当防御 信号。线粒体是这些信号的关键目标。慢性乙醇 治疗影响线粒体功能并增加其易感性 促进细胞凋亡的信号。我们将调查支持和支持的比例是如何 抗细胞凋亡因子在肝脏发病过程中影响线粒体功能 再生以及慢性乙醇治疗如何影响这种平衡。这个 第三个特定目标是解决线粒体在相关的能量应激中的作用 肝部分切除后有肝再生。我们推测增强型 能量需求激活细胞内信号传递过程，导致 线粒体代谢和氧化应激增强。慢性乙醇治疗 降低线粒体对增加的能量需求的反应能力 并增加氧化应激。我们将研究慢性乙醇治疗如何影响 肝部分切除后肝脏的能量状态，导致信号缺陷 这些都是启动肝脏再生所必需的。

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.