Ethanol Effects on the Transcriptional Regulatory Network in Liver Regeneration

项目总结 肝脏再生是一项应用广泛的计划，旨在保持健康的状态 纸巾。当肝脏受到严重损害时，会有一种主动的修复反应，这种反应可以使用 并帮助它们扩展到适合该组织的最佳尺寸。许多毒素和相关治疗都是 能够破坏肝脏组织，以至于只剩下适量的肝功能。然而， 在这些情况下，肝脏在修复其结构和恢复原始组织块方面具有独特的地位 正是这些过程有助于维持肝脏功能，即肝脏再生。修复过程 具有多个生产性应用程序。然而，它可能会因高消耗等过程而脱轨 因此，它受到监测，这可能会破坏其效用。不同寻常的是，我们 最近发现，我们的老鼠暴露在食物中的乙醇会长期导致健康危机 肝脏损伤仅见于雄性大鼠，而雌性大鼠则不受此影响。这一发现与我们之前的发现相符 研究表明，女性对某些类型的酒精相关损伤更具抵抗力。此外， 我们已经制定了一项研究计划，在该计划中，男性会受到各种与酒精有关的伤害， 雌性受到保护，不受。这些发现与肝脏敏感度的单项测试相关。 再生过程在特定的交互中解决。此处总结了具体目标，以使 恢复临界点，以确定问题所在。这些目标包括：(A)研究以检验 酒精影响代谢代偿调节和组织状态平衡的假设 增殖以破坏对PHX的整合反应，(B)研究以检验相互关联的细胞状态的假设 跨多种细胞类型的过渡控制着对乙醇介导的性分裂的综合反应-- 以依赖的方式；和(C)研究以确定乙醇阻断的缺陷的重整化 通过使早期转录调控事件正常化实现肝细胞增殖；我们将在 动物模型和人类ALD通过评估一系列人类的动物研究结果来达到这些目的 确定乙醇作用的共性和可翻译机制以及假定的靶标的ALD条件 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.