Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

乙醇对肝脏再生转录调控网络的影响

• 批准号: 8120873
• 负责人: Joannes B Hoek
• 金额: $ 53.51万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120873
• 关键词: Affect; Alcohol consumption; Alcoholic Liver Diseases; Animal Feed; Biological Assay; Carbohydrates; Cell Cycle; Cell Proliferation; Chronic; Complex; Computer Analysis; Computer Simulation; Control Animal; Data; Development; Diet; Disease; Enzyme-Linked Immunosorbent Assay; Ethanol; Etiology; Evaluation; Experimental Models; Factor Analysis; Fatty acid glycerol esters; Feedback; Gene Expression; Genes; Goals; Hepatocyte; Indium; Injury; Injury to Liver; Intervention; Justice; Kupffer Cells; Liposomes; Liver; Liver Regeneration; Mechanics; Mediating; Mediator of activation protein; Microarray Analysis; Modeling; Natural regeneration; Nature; Network-based; Normal tissue morphology; Partial Hepatectomy; Predisposition; Process; Public Health; Rattus; Recovery; Research; Signal Transduction; Signaling Protein; Small Interfering RNA; Stress; System; TNF gene; Techniques; Testing; Time; Tissues; Transcription factor genes; Validation; Work; alcohol effect; base; chronic alcohol ingestion; effective therapy; experimental analysis; extracellular; feeding; in vivo; insight; intervention effect; nanoparticle; novel; p65; programs; promoter; public health relevance; regenerative; repaired; response; small hairpin RNA; tool; transcription factor

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.

描述（由申请人提供）：慢性酒精摄入会干扰组织损伤后肝再生的发生和进展，这被认为有助于酒精性肝病的发展。我们提出的研究将探讨如何转录调控网络的反应后，部分肝切除术在大鼠慢性酒精摄入量的影响。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）分析从对照和长期乙醇喂养大鼠的肝脏获得的总体基因表达数据得到的转录谱的时间动态，（2）通过采用体内递送小干扰RNA（siRNA）的实验干预来调节转录网络，其靶向关键介质和转录因子，并分析转录网络概况中的相应变化，特别关注由TNF-1和NF-：B网络，以及（3）开发一种计算建模方法，以识别控制网络并驱动再生响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的破坏的性质。我们期望，这种分析将能够提供新的见解，可以做公正的系统性的调节网络在肝再生和放松管制，这个网络的多效性的相互作用所造成的适应长期乙醇消费。 公共卫生关系：该项目的目标是深入了解慢性乙醇治疗干扰肝损伤再生反应的机制，这被认为是酒精性肝病易感性的关键因素。本研究将结合联合收割机的实验和计算模型分析的时间分布的基因表达的变化和潜在的改变，在肝再生过程中的转录因子的活性在慢性乙醇喂养的大鼠和他们的配对喂养的控制部分肝切除术后。