Nrf2, Hepatocyte Proliferation, and Liver Regeneration

描述(由申请人提供)：本提案的总体目标是加深我们对肝细胞增殖反应肝损伤的分子机制的理解。包括肝毒素、药物毒性和病毒感染在内的各种侮辱都会导致急性或慢性肝损伤。然而，肝脏具有非凡的再生能力，可以取代受损的组织，恢复原来的结构和功能。肝细胞作为肝脏的主要结构和功能细胞，在肝组织修复过程中具有极强的复制能力。值得注意的是，肝细胞增殖是肝脏再生的基本过程。适时和/或促进肝细胞增殖可导致肝损伤的恢复和存活，而病理条件下延迟和/或抑制肝细胞增殖可导致肝功能衰竭和死亡。因此，了解肝细胞增殖的调控，对于发展以肝组织修复为靶点的防治肝损伤的治疗手段具有特别重要的意义。形成一个复杂的调控网络，各种生长因子和细胞因子参与调节肝细胞的增殖过程。然而，控制肝细胞增殖以应对肝损伤的确切分子机制仍不清楚。核因子-红系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基因的转录中起核心作用。我们的初步研究表明，Nrf2的激活促进了肝细胞的增殖，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，在部分肝切除(PH)诱导的肝再生过程中，Nrf2被高度激活，而缺乏Nrf2会严重抑制PH后的肝脏生长。这些发现表明，Nrf2参与了肝细胞增殖的调节，以响应肝脏质量的减少。因此，我们的中心假设是Nrf2参与调节肝再生过程中的肝细胞增殖。为了验证这一假设，本文提出了两个具体目标。具体目的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在肝再生过程中对肝细胞增殖和肝生长的影响。拟议的研究将使我们能够更深入地了解肝再生过程中肝细胞增殖的机制。此外，拟议的研究将确立Nrf2在调节肝细胞增殖中的新功能。此外，我们建议的研究将为评估Nrf2作为通过促进肝修复机制治疗肝损伤的新靶点提供必要的信息。公共卫生相关性：拟议的调查将使我们能够更深入地了解肝再生过程中肝细胞增殖的机制。此外，拟议的研究将确立Nrf2在调节肝细胞增殖中的新功能。此外，我们建议的研究将为评估Nrf2作为通过促进肝修复机制治疗肝损伤的新靶点提供必要的信息。

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.