Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

描述(申请人提供)：长期饮酒会干扰组织损伤后肝脏再生的发生和发展，这被认为是导致酒精性肝病的原因之一。我们拟议的研究将检查慢性酒精摄入如何影响大鼠部分肝切除后的转录调控网络反应。我们将使用基因表达和转录因子活性变化的实验分析和计算模型分析相结合的方法来评估对转录调控网络的影响，该网络驱动大鼠肝部分切除后的再生反应。我们的分析将涉及以下目标：(1)分析从对照组和慢性乙醇喂养的大鼠肝脏获得的全球基因表达数据得出的转录图谱的时间动力学；(2)通过在体内传递针对关键介质和转录因子的小干扰RNA(SiRNAs)来调节转录网络，并分析转录网络的相应变化，特别是关注由肿瘤坏死因子-1和核因子：B网络介导的信号；以及(3)开发一种计算建模方法来确定控制网络并驱动再生反应的主要正反馈环和负反馈环。然后，这种计算分析将被用作一种预测工具，以推动进一步的实验工作，并表征长期摄入乙醇造成的反应中断的性质。我们期望这一分析将能够提供新的见解，能够公正地解释肝脏再生过程中调节网络的系统性，以及由于适应长期酒精消费而导致的多效性相互作用对该网络的放松调节。 公共卫生相关性：该项目的目标是深入了解慢性乙醇治疗干扰对肝损伤的再生反应的机制，这被认为是酒精性肝病易感性的关键因素。这项研究将结合实验和计算模型分析慢性酒精喂养的大鼠和其配对喂养的对照大鼠肝部分切除后肝再生过程中基因表达变化的时间分布和转录因子活性的潜在变化。

DESCRIPTION (provided by applicant): Chronic alcohol intake interferes with the onset and progression of liver regeneration after tissue damage, which is thought to contribute to the development of alcoholic liver disease. Our proposed studies will examine how the transcriptional regulatory network response after partial hepatectomy in the rat is affected by chronic alcohol intake. We will use a combination of experimental analysis of gene expression and transcription factor activity changes and computational modeling analysis to evaluate the impact on the transcriptional regulatory network that drive the regenerative response after partial hepatectomy in the rat. Our analysis will involve the following aims: (1) to analyze the temporal dynamics of the transcriptional profile derived from global gene expression data obtained from livers of control and chronically ethanol-fed rats, (2) to modulate the transcriptional network by experimental interventions employing in vivo delivery of small interfering RNAs (siRNAs) that target critical mediators and transcription factors and analyze the corresponding changes in the transcriptional network profile, specifically focusing on signals mediated by TNF-1 and the NF-:B network, and (3) developing a computational modeling approach to identify the major positive and negative feedback loops that control the network and drive the regenerative response. This computational analysis will then be used as a predictive tool to drive further experimental work and characterize the nature of the disruption of the response by chronic ethanol intake. We expect that this analysis will be able to provide novel insights that can do justice to the systemic nature of the regulatory network during liver regeneration and the deregulation of this network by the pleiotropic interactions caused by adaptation to long-term ethanol consumption. PUBLIC HEALTH RELEVANCE: The goal of this project is to gain an in-depth understanding of the mechanisms by which chronic ethanol treatment interferes with the regenerative response to liver damage, which is thought to be a critical element in the susceptibility to alcoholic liver disease. This study will combine an experimental and computational modeling analysis of the temporal profile of gene expression changes and the underlying alterations in activity of transcription factors during the course of liver regeneration after partial hepatectomy in chronically ethanol-fed rats and their pair-fed controls.