Systems Biology of Alcohol Mediated Aberrant Cellular Interactions in the Liver

酒精介导的肝脏异常细胞相互作用的系统生物学

• 批准号: 8835625
• 负责人: Daniel John Cook
• 金额: $ 3.63万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835625
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohols; Animal Feed; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Automobile Driving; Cell Communication; Cell Cycle; Cells; Cereals; Chronic; Cirrhosis; Collection; Communication; Complex; Computer Simulation; Computing Methodologies; Coupled; Data; Diet; Disease; Equilibrium; Gene Expression; Genome; Goals; Hepatectomy; Hepatic Mass; Hepatic Stellate Cell; Hepatitis C; Hepatocyte; Hepatocyte Growth Factor; Hour; Immune; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-6; Kupffer Cells; Lead; Liver; Liver Cirrhosis; Liver Regeneration; Malignant Neoplasms; Measurement; Measures; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Mitogens; Modeling; Molecular; Natural regeneration; Organ; Partial Hepatectomy; Phase; Phenotype; Process; Production; Proteins; Regulation; Regulator Genes; Resolution; Role; Series; Signal Transduction; System; Systems Biology; Testing; Time; Tissues; Toxic effect; Transcriptional Regulation; base; cell type; chronic alcohol ingestion; cytokine; in vivo; inhibitor/antagonist; innate immune function; insight; laser capture microdissection; liver inflammation; liver injury; liver repair; liver transplantation; macrophage; mathematical model; meetings; models and simulation; novel; preempt; prevent; public health relevance; regenerative; research study; stellate cell; tool

DESCRIPTION (provided by applicant): As the body's main detoxifying organ, the liver is exposed to high levels of toxicity and has developed the ability to regenerate following even severe injury. However, chronic alcohol consumption completely inhibits this regenerative ability. Proper function of the innate immune cells and hepatic stellate cells resident within the liver has been shown to be critical in modulating hepatocytes' ability to replicate following tissu damage. Therefore, it is likely that chronic alcohol consumption affects both non-parenchymal cells and hepatocytes. To synthesize this complex system, I have developed a mathematical model of cellular interactions and transcriptional regulation between Kupffer cells, hepatic stellate cells, and hepatocytes during regeneration. The model predicts that alterations to any one component in the system may impair, but not completely inhibit, regeneration. However, if certain combinations of alterations are made to the system, regeneration can be completely inhibited. Specifically, I predicts that altered inflammation following partial hepatectomy coupled with hypersensitive or hyperactive hepatic stellate cells leads to complete inhibition of regeneration. Additionally, model simulations suggest that these effects should be observable during and shortly after the priming phase of regeneration (0-6 hrs post-hepatectomy). Although these mechanisms have not been previously studied in the context of chronic alcohol consumption's inhibition of liver repair, chronic alcohol consumption has been shown to alter the inflammatory state of the liver and may progress to cirrhosis, a diseased characterized by highly activated stellate cells. Therefore the goal of this project is to characterize and understand how dynamic alterations in cytokine microenvironment and hepatic stellate cell activation within the liver during the early phases of regeneration contribute to deficient liver regeneration by testing the following hypotheses: (1) chronic alcohol consumption dynamically shifts the balance of pro-inflammatory and anti-inflammatory liver cytokines following partial hepatectomy (PHx), leading to reduced hepatocyte priming, and (2) chronic alcohol consumption dynamically shifts hepatic stellate cells (HSCs) into a distinguishable anti-regenerative activation phenotype post-partial hepatectomy, thereby altering the balance between pro-regenerative and anti- regenerative hepatic stellate cells. Based on model predictions and preliminary results, we expect to find that chronic alcohol consumption increases IL-10 production and decreases or delays IL-6 production leading to a reduction in hepatocyte priming during the priming phase of regeneration. We also expect that chornic alcohol consumption shifts the balance of HSC from a mainly pro-regenerative activation state to a mainly anti-regenerative activation state in the earl phases of regeneration (observable by 6 hrs and peaking at 12 hrs post-PHx). Using systems-tools to investigate the contributions of non-parenchymal cells to an animal model of liver repair will allow integration of these less-studied aspects of liver adaptation to alcohol with the larger field of liver alcohol-adaptation including genome-scale gene expression, hepatocyte signaling, and miRNA-based studies. Additionally, the computational modeling-based approach used in this study will allow for interpretation of our molecular mechanistic findings in the context of alcohol-induced changes to non-parenchymal cell activation phenotype impacting regeneration at a whole-tissue scale.

描述（由申请人提供）：作为人体主要的解毒器官，肝脏暴露于高水平的毒性下，并且在严重损伤后具有再生能力。然而，长期饮酒会完全抑制这种再生能力。肝脏内固有免疫细胞和肝星状细胞的正常功能已被证明对于调节组织损伤后肝细胞的复制能力至关重要。因此，长期饮酒可能会影响非实质细胞和肝细胞。为了合成这个复杂的系统，我开发了再生过程中库普弗细胞、肝星状细胞和肝细胞之间的细胞相互作用和转录调节的数学模型。该模型预测，系统中任何一个组件的改变都可能损害但不会完全抑制再生。然而，如果对系统进行某些改变组合，再生可能会被完全抑制。具体来说，我预测部分肝切除术后炎症的改变与 与过敏或过度活跃的肝星状细胞一起导致再生的完全抑制。此外，模型模拟表明，这些效应应该在再生启动阶段（肝切除术后 0-6 小时）期间和之后不久即可观察到。尽管之前尚未在长期饮酒抑制肝脏修复的背景下研究过这些机制，但长期饮酒已被证明会改变肝脏的炎症状态，并可能进展为肝硬化，这是一种以高度活化的星状细胞为特征的疾病。因此，该项目的目标是通过测试来表征和了解再生早期阶段肝脏内细胞因子微环境和肝星状细胞活化的动态变化如何导致肝再生缺陷 以下假设：（1）慢性饮酒动态改变部分肝切除术（PHx）后促炎性和抗炎性肝细胞因子的平衡，导致肝细胞启动减少，（2）长期饮酒动态地将肝星状细胞（HSC）转变为部分肝切除术后可区分的抗再生激活表型， 从而改变促再生和抗再生肝星状细胞之间的平衡。根据模型预测和初步结果，我们预计长期饮酒会增加 IL-10 的产生，并减少或延迟 IL-6 的产生，从而导致再生启动阶段肝细胞启动的减少。我们还预计，在再生的早期阶段，慢性酒精消耗会将 HSC 的平衡从主要是促再生的激活状态转变为主要是抗再生的激活状态（可在 PHx 后 6 小时观察到，在 PHx 后 12 小时达到峰值）。使用系统工具来研究非实质细胞对肝脏修复动物模型的贡献，将允许将肝脏对酒精适应的这些研究较少的方面与更大的肝脏适应相结合。 肝脏酒精适应领域，包括基因组规模的基因表达、肝细胞信号传导和基于 miRNA 的研究。此外，本研究中使用的基于计算模型的方法将允许在酒精诱导的非实质细胞活化表型变化影响整个组织规模再生的背景下解释我们的分子机制发现。