Nrf2, Hepatocyte Proliferation, and Liver Regeneration

Nrf2、肝细胞增殖和肝脏再生

• 批准号: 8444465
• 负责人: GUOLI DAI
• 金额: $ 25.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444465
• 关键词: Acute; Affect; Antioxidants; Binding; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Cessation of life; Chronic; Complex; DNA biosynthesis; Drug Targeting; Drug toxicity; Electrophoretic Mobility Shift Assay; Enzymes; G2/M Transition; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Hepatic Mass; Hepatocyte; In Vitro; Injury to Liver; Investigation; Knockout Mice; Liver; Liver Failure; Liver Regeneration; Mitosis; Molecular; Natural regeneration; Partial Hepatectomy; Pathway interactions; Pharmaceutical Preparations; Phase; Phosphotransferases; Play; Prevention; Process; Proteins; Recovery; Regulation; Reporter; Response Elements; Role; S Phase; Structure; System; Testing; Tetanus Helper Peptide; Therapeutic; Time; Tissues; Virus Diseases; base; circadian pacemaker; cyclin-dependent kinase inhibitor 1B; cytokine; functional status; hepatotoxin; in vivo; insight; liver cell proliferation; liver injury; liver repair; novel; nuclear factor-erythroid 2; promoter; research study; response; tissue repair; transcription factor

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.

抽象的 该提案的总体目标是进一步了解控制的分子机制 肝细胞增殖响应肝损伤。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， 更换受损组织并恢复原有结构和功能。肝细胞作为主要结构细胞 肝脏中的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，肝细胞增殖构成了肝脏再生的基本过程。及时和/或 增强的肝细胞增殖导致肝损伤恢复和存活，而延迟和/或 在病理条件下抑制肝细胞增殖会导致肝衰竭和死亡。所以， 了解肝细胞增殖的调节对于开发治疗方法特别重要 是指以肝组织修复为目标，预防和治疗肝损伤。形成复杂的监管体系 网络中，各种生长因子和细胞因子参与调节增殖过程 肝细胞。然而，控制肝细胞增殖的精确分子机制 肝损伤的定义仍不明确。 核因子-红细胞 2 p45 相关因子 2 (Nrf2) 是一种转录因子，在 调节编码药物解毒酶和抗氧化蛋白的基因的转录。我们的 初步研究表明，Nrf2 激活可刺激肝细胞增殖，这代表了一种新的机制。 该转录因子的功能。此外，我们的初步研究表明 Nrf2 高度 在部分肝切除术 (PH) 诱导的肝再生过程中被激活，Nrf2 的缺乏会导致严重的肝损伤。 PH 后抑制肝脏生长。这些发现表明 Nrf2 参与调节肝细胞 肝脏质量损失导致的增殖。因此，我们的中心假设是 Nrf2 参与 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： 建议的。具体目标1：确定Nrf2调节肝细胞的分子机制 增殖。具体目标 2：确定 Nrf2 药理学激活对肝细胞的影响 肝再生过程中的增殖和肝脏生长。 拟议的研究将使我们能够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，拟议的研究将建立 Nrf2 的新功能 调节肝细胞增殖。此外，我们提出的研究将为以下人员提供重要信息： 评估Nrf2作为通过增强肝修复机制治疗肝损伤的新靶点。

项目成果

Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration.

• DOI: 10.1152/ajpgi.00332.2014
• 发表时间: 2015-02
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Yuhong Zou;Min Hu;Joonyong Lee;S. M. Nambiar;Veronica Garcia;Q. Bao;J. Chan;G. Dai

Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration.

在部分肝切除诱导的肝再生过程中，四波肝细胞增殖与三波肝脂肪积累相关。

• DOI: 10.1371/journal.pone.0030675
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zou,Yuhong;Bao,Qi;Kumar,Sudhanshu;Hu,Min;Wang,Guo-Ying;Dai,Guoli
• 通讯作者: Dai,Guoli

Nuclear Factor Erythroid 2-Related Factor 2 Deficiency Results in Amplification of the Liver Fat-Lowering Effect of Estrogen.

• DOI: 10.1124/jpet.115.231316
• 发表时间: 2016-07-01
• 期刊: The Journal of pharmacology and experimental therapeutics
• 作者: Rui, Wenjuan;Zou, Yuhong;Dai, Guoli
• 通讯作者: Dai, Guoli

Proteomic analysis of immediate-early response plasma proteins after 70% and 90% partial hepatectomy.

70％和90％部分肝切除术后立即反应血浆蛋白的蛋白质组学分析。

• DOI: 10.1111/hepr.12030
• 发表时间: 2013-08
• 期刊: Hepatology research : the official journal of the Japan Society of Hepatology
• 作者: Kumar S;Zou Y;Bao Q;Wang M;Dai G
• 通讯作者: Dai G

Nrf2 is involved in maintaining hepatocyte identity during liver regeneration.

• DOI: 10.1371/journal.pone.0107423
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zou Y;Lee J;Nambiar SM;Hu M;Rui W;Bao Q;Chan JY;Dai G
• 通讯作者: Dai G