Control of drug and ethanol metabolism

描述（由申请人提供）：我们已经确定了一种新的潜在机制，酒精导致肝损伤。具体地说，我们发现，肝纤维蛋白溶酶原激活物抑制剂-1（派-1）的表达上调乙醇和表达水平与肠内酒精模型对肝损伤的保护。此外，我们发现派-1-/-小鼠不仅可以防止酒精引起的脂肪肝，还可以防止疾病的后期阶段（炎症，坏死和纤维化）。因此，我们推测派-1上调在ALD中起因果作用。我们将通过以下具体目标来建立这一假设。1)派-1是否参与小鼠肠内酒精性肝损伤？我们将通过研究抑制派-1表达对肠内小鼠模型中酒精所致肝损伤的影响来直接检验这一假设。待检验的具体亚假设是：a）派-1的缺乏将保护小鼠免受实验性ALD，B）派-1通过受损的VLDL合成介导酒精后的脂肪变性，c）派-1通过纤维蛋白沉积介导慢性酒精暴露期间的肝脏炎症。2.确定酒精诱导派-1的机制。这个特定目标的目的是确定派-1是由慢性酒精诱导的主要机制。待检验的具体亚假设是：a）TNF α是由于乙醇引起的派-1的主要诱导物。B）派-1由酒精通过涉及受损的肝胰岛素信号传导的机制诱导。3)为了确定派-1介导肝纤维化的机制，我们将建立在初步研究的基础上，测试派-1在肝纤维化中也起因果作用的假设。待测试的具体亚假设是：a）派-1-/-小鼠在基质分解水平上免受肝纤维化，B）派-1-/-小鼠中增强的基质分解需要基质金属蛋白酶，c）派-1的抑制将增强从已建立的纤维化和肝硬化的恢复。总之，我们期望这项工作的结果能够在早期损伤（脂肪变性，炎症和坏死）以及疾病的后期阶段（即，纤维化和肝硬化）。因此，我们期望这项工作的结果将确定靶向派-1作为ALD的新的潜在治疗方法。

DESCRIPTION (provided by applicant): We have identified a novel potential mechanism by which alcohol causes liver damage. Specifically, we showed that hepatic expression of plasminogen activator inhibitor-1 (PAI-1) is upregulated by ethanol and the level of expression correlates with protection against liver damage in enteral alcohol model. Furthermore, we showed that PAI-1-/- mice are protected against not only fatty liver due to alcohol, but also later stages of the disease (inflammation, necrosis and fibrosis). We therefore hypothesize that PAI-1 upregulation plays a causal role in ALD. We will build on this hypothesis via the following specific aims. 1) Is PAI-1 involved in enteral alcohol-induced liver injury in mice? We will directly test this hypothesis by investigating the effect of inhibition of PAI-1 expression on liver damage due to alcohol in the enteral mouse model. Specific subhypotheses to be tested are: a) Absence of PAI-1 will protect against experimental ALD in mice, b) PAI-1 mediates steatosis after alcohol via impaired VLDL synthesis, c) PAI-1 mediates hepatic inflammation during chronic alcohol exposure via fibrin deposition. 2. To determine the mechanism(s) by which PAI-1 is induced by alcohol. The purpose of this specific aim is to identify the major mechanisms by which PAI-1 is induced by chronic alcohol. Specific subhypotheses to be tested are: a) TNFa is the major inducer of PAI-1 due to ethanol. b) PAI-1 is induced by alcohol via mechanisms involving impaired hepatic insulin signaling. 3) To determine the mechanism(s) by which PAI-1 mediates hepatic fibrosis we will build on Preliminary Studies testing the hypothesis that PAI-1 also plays a causal role in hepatic fibrosis. Specific subhypotheses to be tested are: a) PAI-1-/- mice are protected against hepatic fibrosis at the level of matrix resolution, b) Matrix metalloproteases are required for enhanced matrix resolution in PAI-1-/- mice, c) Inhibition of PAI-1 will enhance recovery from established fibrosis and cirrhosis. Taken together, we expect the results of this work to identify a new causal role of PAI-1 in alcoholic liver injury at the level of early damage (steatosis, inflammation and necrosis), as well as in later stages of the disease (i.e., fibrosis and cirrhosis). We therefore expect that the results of this work will identify targeting PAI-1 as a new potential therapy for ALD.