Ethanol-mediated inhibition of the S1P lyase results in disruption of apoptotic machinery and lymphocyte egress from lymphoid tissue

 描述（由申请人提供）：已知慢性或重复性酗酒会导致酒精性肝病（ALD），其包括几种不同的表型（例如，肝硬化、脂肪肝、肝炎和肝癌易感性）。此外，酗酒者通常免疫功能低下，因此面临机会性病原体额外挑战的风险更高。虽然这些组织损伤的例子得到了很好的研究，但对潜在的细胞机制的解释仍然不太清楚。此外，这些快速和短暂的细胞后果的相关性还没有得到显着解决酗酒模型。这项工作的目的是调查乙醇对鞘脂代谢途径的影响，并研究这种相互作用的结果发生的表型。使用遗传修饰的细胞培养或体内小鼠模型的乙醇暴露，我们的目标是解决机制，改变细胞内。我们将集中在两个特定的情况下，研究乙醇介导的鞘脂途径的调制的结果。(1)我们将利用ALD和原代鼠肝细胞的细胞培养模型来研究乙醇介导的鞘脂代谢抑制对细胞凋亡机制的破坏。我们还将使用来自生物储存库的人类样本的组织学来验证我们的发现。(2)我们将描述由于乙醇影响淋巴细胞从淋巴结和胸腺中排出而导致的鞘脂代谢抑制的性质。将对这些小鼠的组织、血清和淋巴液进行分离，以评估关键酶、脂质和成熟淋巴细胞的水平。这些目标的完成将有助于导致与ALD相关的慢性表型的潜在细胞机制。此外，这种对乙醇反应的新观点将为治疗药物带来新的机会，以减轻酒精成瘾患者的某些疾病。

 DESCRIPTION (provided by applicant): Chronic or repetitive binge alcohol consumption is known to lead to alcoholic liver disease (ALD) which encompasses several different phenotypes (e.g., cirrhosis, fatty liver disease, hepatitis, and susceptibility to liver cancer). Additionally alcoholics are routinely immuno-compromised and therefore at heightened risk for additional challenges from opportunistic pathogens. While these examples of tissue damage are well studied, explanations of the underlying cellular mechanisms remain less clear. Furthermore, the relevance of these rapid and transient cellular consequences have not been significantly addressed in binge models of alcohol consumption. The goal of this work is to investigate the effect of ethanol on the sphingolipid metabolic pathway, and study the phenotypes that occur as a result of this interaction. Using genetically modified cell culture or in vivo mouse models of ethanol exposure, we aim to address the mechanisms that alter within the cell. We will focus on two particular contexts to study the outcome of ethanol-mediated modulation of the sphingolipid pathway. (1) We will utilize cell culture models of ALD and primary murine hepatocytes to study disruptions to apoptotic machinery as a consequence of ethanol-mediated inhibition of sphingolipid metabolism. We will also validate our findings using histology of human samples from a biorepository. (2) We will characterize the nature by which sphingolipid metabolism inhibition due to ethanol effects lymphocyte egress from lymph nodes and the thymus. Isolations of tissues, serum, and lymph in these mice will conducted to assess levels of critical enzymes, lipids, and mature lymphocytes. Completion of these aims will aid in the underlying cellular mechanisms that result in the chronic phenotypes associated with ALD. Additionally, this new perspective on ethanol response will result in new opportunities for therapeutics to alleviate some of these diseases in patients suffering from addiction to alcohol.