Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

项目摘要 肝再生是一个程序，具有广泛的应用，旨在保持健康的状态， 组织。当肝脏受到严重损伤时，会有一种积极的修复反应，可以使用 功能细胞，并帮助它们扩展到该组织的最佳尺寸。许多毒素和相关的治疗是 能够损害肝组织到仅保留少量肝功能的程度。然而，在这方面， 在这些条件下，肝脏处于独特的位置，以修复其结构并恢复原始组织块， 正是这些过程帮助维持肝脏功能，称为肝脏再生。修复过程 具有多种生产应用。然而，它可能会因大量消费等过程而脱轨 因此，它受到监控，这可能会破坏其有用性。不寻常的是，我们 最近发现，我们的老鼠暴露于食物中的乙醇会长期导致健康危机， 肝损伤只发生在雄性大鼠中，而雌性大鼠没有遭受这种痛苦。这一发现与我们先前的 研究表明，女性对某些类型的酒精相关伤害的抵抗力更强。此外，委员会认为， 我们已经开发了一个研究项目，在这个项目中，男性受到各种与酒精有关的伤害， 女性受到保护。这些发现与肝脏敏感性的个体试验相关 再生过程在特定的相互作用中解决。具体目标总结如下， 关键点的恢复，以确定问题所在。这些目标包括：（a）进行研究， 假设乙醇影响代谢代偿调节的组织状态平衡， （B）研究以检验互连的细胞状态 跨多种细胞类型的转换控制了性别中对乙醇介导的破坏的整合反应， 依赖的方式;和（c）研究，以确定重整的乙醇阻断的缺陷， 通过使早期转录调控事件正常化来促进肝细胞增殖; 动物模型和人类ALD的研究结果， ALD条件，以确定乙醇作用的共同点和可转化机制以及 干预

PROJECT SUMMARY Liver regeneration is a program with a broad range of applications that is designed to maintain a healthy state of the tissue. When the liver gets exposed to severe damage, there is an active repair response that can use the functional cells and help them expand to the optimal size for that tissue. Many toxins and related treatments are capable of damaging the liver tissue to the point where only a modest quantity of liver function remains. However, under these conditions the liver is uniquely positioned to repair its structure and recover the original tissue mass and it is these processes that help maintain liver function, referred to as Liver Regeneration. The repair process has multiple productive applications. However, it may be derailed by processes such as the heavy consumption of alcoholic beverages and as a result, it is subject to monitoring that may derail its usefulness. Unusually, we recently discovered that exposure of our rats to ethanol in their food will chronically lead to a health crisis upon liver injury only in male rats, whereas female rats did not suffer from this affliction. This finding matched our prior studies that had demonstrated that females are more resistant to some types of alcohol-related injury. Moreover, we have developed a research program in which males are subject to a variety of alcohol-related injuries that females are protected from. These findings are correlated with the individual tests for sensitivity of the liver regeneration process resolved in specific interactions. The Specific Aims are summarized here to enable the recovery of the critical points to identify where the problems are located. These aims include (a) studies to test the hypothesis that ethanol affects the tissue state balance of metabolic compensatory adjustments and proliferation to disrupt the integrate response to PHx, (b) studies to test the hypothesis that interlinked cell state transitions across multiple cell types govern the integrative response to ethanol-mediated disruption in a sex- dependent manner; and (c) studies to identify the renormalization of the ethanol-blocked deficiencies in hepatocyte proliferation by normalizing early phase transcriptional regulatory events; We will bridge between animal models and human ALD in these Aims by evaluating the animal study results across a spectrum of human ALD conditions to identify commonalities and translatable mechanisms of ethanol action and putative targets for intervention.