Nrf2, Hepatocyte Proliferation, and Liver Regeneration

摘要 这项建议的总体目标是进一步了解分子机制， 肝细胞增殖对肝损伤的反应。各种损伤，包括肝毒素、药物毒性和 病毒感染引起急性或慢性肝损伤。然而，肝脏具有非凡的再生能力， 替换受损组织并恢复原始结构和功能。肝细胞作为主要的结构细胞， 和功能性细胞，在肝脏组织修复过程中具有极强的复制能力。 值得注意的是，肝细胞增殖构成了肝再生的基本过程。及时和/或 增强的肝细胞增殖导致从肝损伤和存活中恢复，而延迟和/或 在病理条件下抑制肝细胞增殖导致肝衰竭和死亡。因此，我们认为， 了解肝细胞增殖的调节在开发治疗性药物中特别重要。 指靶向肝组织修复以预防和治疗肝损伤。形成复杂的监管体系 网络，各种生长因子和细胞因子参与调节细胞增殖过程。 肝细胞然而，控制肝细胞增殖的精确分子机制是对肝细胞增殖的反应。 肝损伤的定义仍不明确。 核因子-红细胞2 p45相关因子2（Nrf 2）是一种转录因子，在细胞凋亡中起核心作用。 调节编码药物解毒酶和抗氧化蛋白的基因的转录。我们 初步研究表明，Nrf 2激活刺激肝细胞增殖，这代表了一种新的 这个转录因子的功能。此外，我们的初步研究表明，Nrf 2是高度 在部分肝切除术（PH）诱导的肝再生过程中激活，并且缺乏Nrf 2导致严重的 这些结果表明，Nrf 2参与调节肝细胞的生长， 增殖反应肝脏质量损失。因此，我们的中心假设是Nrf 2参与了 在肝再生过程中调节肝细胞增殖。为了检验这一假设，有两个具体目标： 提出了具体目标1：确定Nrf 2调节肝细胞的分子机制 增殖具体目的2：确定Nrf 2的药理学活化对肝细胞的影响 增殖和肝再生过程中的肝生长。 这项研究将使我们更深入地了解肝细胞的调控机制， 肝再生过程中的增殖。此外，所提出的研究将建立Nrf 2的新功能 调节肝细胞增殖。此外，我们建议的研究将提供必要的资料， 评估Nrf 2作为通过增强肝脏修复的机制治疗肝损伤的新靶点。

ABSTRACT The overall goal of this proposal is to further our understanding of the molecular mechanisms governing hepatocyte proliferation in response to liver injury. Various insults including hepatotoxins, drug toxicity, and viral infection cause acute or chronic liver injury. However, the liver has an extraordinary ability to regenerate, replacing damaged tissue and restoring original structures and functions. Hepatocytes, as the main structural and functional cells in the liver, are extremely capable of replicating during liver tissue repair process. Remarkably, hepatocyte proliferation constitutes the fundamental process of liver regeneration. Timely and/or enhanced hepatocyte proliferation leads to recovery from liver injury and survival, whereas delayed and/or inhibited hepatocyte proliferation in pathological conditions results in liver failure and death. Therefore, understanding the regulation of hepatocyte proliferation is of particular importance in developing therapeutic means targeting liver tissue repair for prevention and treatment of liver injury. Forming a complex regulatory network, various growth factors and cytokines participate in modulating the proliferative process of hepatocytes. However, the precise molecular mechanisms that control hepatocyte proliferation in response to liver injury remain poorly defined. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a transcription factor that plays a central role in regulating the transcription of genes encoding drug-detoxifying enzymes and antioxidant proteins. Our preliminary studies revealed that Nrf2 activation stimulates hepatocyte proliferation, which represents a novel function of this transcription factor. Furthermore, our preliminary studies demonstrated that Nrf2 is highly activated during partial hepatectomy (PH)-induced liver regeneration and lack of Nrf2 leads to severely suppressed liver growth after PH. These findings suggest that Nrf2 participates in modulating hepatocyte proliferation in response to liver mass loss. Therefore, our central hypothesis is that Nrf2 participates in regulating hepatocyte proliferation during liver regeneration. To test this hypothesis, two specific aims are proposed. Specific Aim 1: determine the molecular mechanisms by which Nrf2 regulates hepatocyte proliferation. Specific Aim 2: determine the effects of pharmacological activation of Nrf2 on hepatocyte proliferation and liver growth during liver regeneration. The proposed investigation will enable us to gain greater insight into the mechanisms governing hepatocyte proliferation during liver regeneration. Moreover, the proposed studies will establish the novel function of Nrf2 in regulating hepatocyte proliferation. Furthermore, our proposed studies will provide essential information to evaluate Nrf2 as a novel target for treatment of liver injury through a mechanism of enhancing liver repair.