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脏再生的发作和进展，这被认为有助于酒精性肝病的发展。我们提出的研究将研究大鼠部分肝切除术后的转录调节网络反应如何受到慢性酒精摄入的影响。我们将使用对基因表达和转录因子活性变化和计算模型分析的实验分析的组合来评估对大鼠部分肝切除术后驱动再生反应的转录调节网络的影响。我们的分析将涉及以下目的：（1）分析从对照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曲线的时间动态，（2），通过实验性干预措施调节转录介绍，这些干预措施采用了转移型的转移型和分析的批判性介绍和分析，并分析了批判性的介绍和分析，并分析了详尽的介绍，并分析了详细介绍的范围。专注于由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，以识别控制网络并驱动再生响应的主要正和负反馈循环。然后，该计算分析将用作推动进一步实验工作并表征慢性乙醇摄入反应破坏的性质的预测工具。我们预计，这种分析将能够提供新颖的见解，可以在肝脏再生过程中对调节网络的系统性和通过对长期乙醇消耗所引起的多效性相互作用对该网络的放松管制。 公共卫生相关性：该项目的目的是深入了解慢性乙醇治疗对肝脏损害的再生反应的机制，这被认为是对酒精性肝病易感性的关键因素。这项研究将结合对基因表达变化的时间分布的实验和计算模型分析，以及在肝脏再生术中肝脏再生过程中转录因子活性的潜在变化，在慢性乙醇喂养的大鼠及其成对的对照中。