Nrf2, Hepatocyte Proliferation, and Liver Regeneration

描述（由申请人提供）：本提案的总体目标是进一步了解肝损伤后肝细胞增殖的分子机制。包括肝毒素、药物毒性和病毒感染在内的各种损害可引起急性或慢性肝损伤。然而，肝脏具有非凡的再生能力，可以替换受损的组织，恢复原有的结构和功能。肝细胞作为肝脏中主要的结构细胞和功能细胞，在肝组织修复过程中具有极强的复制能力。值得注意的是，肝细胞增殖是肝再生的基本过程。及时和/或增强肝细胞增殖导致肝损伤的恢复和生存，而病理条件下延迟和/或抑制肝细胞增殖导致肝功能衰竭和死亡。因此，了解肝细胞增殖的调控，对于开发针对肝组织修复的治疗手段，预防和治疗肝损伤具有特别重要的意义。多种生长因子和细胞因子参与调节肝细胞的增殖过程，形成一个复杂的调控网络。然而，控制肝细胞增殖以应对肝损伤的精确分子机制仍然不明确。核因子-红细胞2 p45相关因子2 （Nrf2）是一种转录因子，在调节药物解毒酶和抗氧化蛋白编码基因的转录中起核心作用。我们的初步研究表明Nrf2激活刺激肝细胞增殖，这代表了该转录因子的一种新功能。此外，我们的初步研究表明，Nrf2在部分肝切除术（PH）诱导的肝脏再生过程中高度激活，缺乏Nrf2会导致PH后肝脏生长严重抑制。这些研究结果表明，Nrf2参与调节肝细胞增殖，以应对肝质量损失。因此，我们的中心假设是Nrf2在肝脏再生过程中参与调节肝细胞增殖。为了验证这一假设，提出了两个具体目标。特异性目的1：确定Nrf2调控肝细胞增殖的分子机制。特异性目的2：确定Nrf2的药理激活对肝再生过程中肝细胞增殖和肝脏生长的影响。这项拟议的研究将使我们能够更深入地了解肝脏再生过程中肝细胞增殖的机制。此外，所提出的研究将建立Nrf2在调节肝细胞增殖中的新功能。此外，我们提出的研究将提供必要的信息，通过增强肝脏修复的机制来评估Nrf2作为治疗肝损伤的新靶点。公共卫生相关性：拟议的研究将使我们能够更深入地了解肝脏再生过程中控制肝细胞增殖的机制。此外，所提出的研究将建立Nrf2在调节肝细胞增殖中的新功能。此外，我们提出的研究将提供必要的信息，通过增强肝脏修复的机制来评估Nrf2作为治疗肝损伤的新靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.