Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

描述（由申请人提供）：慢性酒精摄入干扰组织损伤后肝脏再生的发生和进展，这被认为是导致酒精性肝病发展的原因。我们提出的研究将研究慢性酒精摄入如何影响大鼠部分肝切除术后的转录调节网络反应。我们将结合基因表达和转录因子活性变化的实验分析和计算建模分析来评估对大鼠部分肝切除术后驱动再生反应的转录调控网络的影响。我们的分析将涉及以下目标：(1)分析从对照组和长期乙醇喂养大鼠肝脏获得的全局基因表达数据得出的转录谱的时间动态；(2)通过实验干预，利用体内递送靶向关键介质和转录因子的小干扰rna （sirna）来调节转录网络，并分析转录网络谱的相应变化；特别关注由TNF-1和NF-:B网络介导的信号，以及(3)开发一种计算建模方法来识别控制网络和驱动再生反应的主要正反馈和负反馈回路。然后，这种计算分析将被用作预测工具，以推动进一步的实验工作，并表征慢性乙醇摄入对反应破坏的性质。我们期望这一分析能够提供新的见解，能够公正地处理肝脏再生过程中调节网络的系统性质，以及由于适应长期乙醇消耗而引起的多效性相互作用对该网络的放松管制。

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.