Nrf2, Hepatocyte Proliferation, and Liver Regeneration

Nrf2、肝细胞增殖和肝脏再生

• 批准号: 8037578
• 负责人: GUOLI DAI
• 金额: $ 26.41万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037578
• 关键词: Acute; Affect; Antioxidants; Binding; Cell Cycle; Cell Cycle Progression; Cell Proliferation; Cells; Cessation of life; Chronic; Complex; DNA biosynthesis; Drug Delivery Systems; Drug toxicity; Electrophoretic Mobility Shift Assay; Enzymes; G2/M Transition; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Health; Hepatic Mass; Hepatocyte; In Vitro; Injury; 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; Wound Healing; base; circadian pacemaker; cyclin-dependent kinase inhibitor 1B; cytokine; functional status; hepatotoxin; in vivo; insight; liver cell proliferation; novel; nuclear factor-erythroid 2; promoter; repaired; research study; response; transcription factor

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.

描述（由申请人提供）：该提案的总体目标是进一步了解控制肝细胞增殖以应对肝损伤的分子机制。包括肝毒素、药物毒性和病毒感染在内的各种损伤会导致急性或慢性肝损伤。然而，肝脏具有非凡的再生能力，可以替换受损的组织并恢复原有的结构和功能。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，而在病理条件下延迟和/或抑制肝细胞增殖导致肝衰竭和死亡。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来预防和治疗肝损伤显得尤为重要。各种生长因子和细胞因子形成复杂的调节网络，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精确分子机制仍不清楚。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转录中发挥核心作用。我们的初步研究表明，Nrf2 激活可刺激肝细胞增殖，这代表了该转录因子的新功能。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，而 Nrf2 的缺乏会导致 PH 后肝脏生长严重受到抑制。这些发现表明 Nrf2 参与调节肝细胞增殖以响应肝脏质量损失。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。为了检验这一假设，提出了两个具体目标。具体目标1：确定Nrf2调节肝细胞增殖的分子机制。具体目标 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。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，拟议的研究将确定 Nrf2 在调节肝细胞增殖中的新功能。此外，我们提出的研究将为评估 Nrf2 作为通过增强肝脏修复机制治疗肝损伤的新靶点提供重要信息。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，拟议的研究将确定 Nrf2 在调节肝细胞增殖中的新功能。此外，我们提出的研究将为评估 Nrf2 作为通过增强肝脏修复机制治疗肝损伤的新靶点提供重要信息。