Systems Biology of Alcohol Mediated Aberrant Cellular Interactions in the Liver

描述（由申请人提供）：肝脏作为人体主要的排毒器官，暴露在高水平的毒性中，即使在严重损伤后也具有再生能力。然而，长期饮酒完全抑制了这种再生能力。肝脏内固有免疫细胞和肝星状细胞的正常功能已被证明在组织损伤后调节肝细胞复制能力方面至关重要。因此，长期饮酒可能同时影响非实质细胞和肝细胞。为了合成这个复杂的系统，我建立了一个数学模型，描述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。该模型预测，对系统中任何一个组成部分的改变都可能损害，但不会完全抑制再生。然而，如果对系统进行某些改变组合，再生可以完全被抑制。具体来说，我预测在部分肝切除术和

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.