Control of drug and ethanol metabolism

描述（由申请人提供）：我们已经确定了酒精导致肝损伤的一种新的潜在机制。具体来说，我们发现在肠内酒精模型中，乙醇上调了纤溶酶原激活物抑制剂-1 （PAI-1）的肝脏表达，其表达水平与肝损伤保护相关。此外，我们发现PAI-1-/-小鼠不仅可以预防酒精引起的脂肪肝，还可以预防疾病的后期阶段（炎症、坏死和纤维化）。因此，我们假设PAI-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) PAI-1是否参与小鼠肠内酒精性肝损伤？我们将通过在小鼠肠内模型中研究抑制PAI-1表达对酒精肝损伤的影响来直接验证这一假设。有待验证的具体子假设有：a)缺乏PAI-1将保护小鼠免受实验性ALD， b) PAI-1通过损害VLDL合成介导酒精后脂肪变性，c) PAI-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PAI-1的机制。这一特定目的的目的是确定慢性酒精诱导PAI-1的主要机制。需要验证的具体子假设有：a) TNFa是乙醇引起的PAI-1的主要诱导剂。b)酒精通过肝胰岛素信号通路受损的机制诱导PAI-1。3)为了确定PAI-1介导肝纤维化的机制，我们将建立在初步研究的基础上，验证PAI-1在肝纤维化中也起因果作用的假设。需要测试的具体子假设有：a)在基质分解水平上，PAI-1-/-小鼠可以防止肝纤维化；b)增强PAI-1-/-小鼠的基质分解需要基质金属蛋白酶；c)抑制PAI-1将增强已建立的纤维化和肝硬化的恢复。综上所述，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）以及疾病后期（即纤维化和肝硬化）的水平上确定PAI-1在酒精性肝损伤中的新的因果作用。因此，我们期望这项工作的结果将确定靶向PAI-1作为一种新的潜在治疗ALD的方法。

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.