Role of Nod2 and AMP-kinase in obesity-associated liver cancer

Nod2 和 AMP 激酶在肥胖相关肝癌中的作用

基本信息

  • 批准号:
    10512198
  • 负责人:
  • 金额:
    $ 7.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Liver cancer is one of the fastest increasing causes of cancer-related deaths in the U.S. and worldwide. There are approximately 700,000 deaths worldwide each year due to liver cancer. Risk factors for liver cancer include nonalcoholic fatty liver disease, diabetes, and obesity, and the rising incidence in these diseases is paralleled with an increasing incidence in liver cancer. The development of hepatocellular carcinoma, the major subtype of liver cancer, is a multistep process and often starts with chronic inflammation. However, the molecular and cellular causes of inflammation remain poorly understood. Nod2 is a bacterial innate immunity protein and Nod2 deficiency is associated with inflammatory diseases, diet-induced obesity and metabolic dysfunction, and obesity-dependent liver cancer. Preliminary data, using a mouse model for hepatocellular carcinoma, predicts that the development of liver tumorigenesis in Nod2-deficient mice on high fat diet (HFD) is associated with an inhibition of the AMP- dependent kinase (AMPK) pathway. AMPK is a master regulator of metabolic reprogramming and cell proliferation. However, the role of the AMPK pathway in liver tumorigenesis in Nod2-deficient mice has not been demonstrated. In the current project, the hypothesis that there is decreased activation of the AMPK pathway in Nod2-/- tumorigenic mice, which contributes to the development of hepatic tumors in these mice will be tested. In Aim 1, the role of Nod2 in the activation of the AMPK pathway will be determined. WT and Nod2-/- mice will be treated with the carcinogen dimethylbenz[a]anthracene (DMBA) and maintained on HFD (DMBA+HFD) to induce liver tumors and regulation of proteins in the AMPK pathway will be determined in the liver. In Aim 2, the role of the AMPK pathway in the development of obesity-dependent hepatic tumors in Nod2-/- mice will be determined. Nod2-/- DMBA+HFD mice will be treated with metformin to activate AMPK and monitored for the development of hepatic tumors. The results from these experiments will provide proof-of-concept for the role of Nod2 in activation of the AMPK pathway and for the role of this pathway in protection from the development of hepatocellular carcinoma and will provide preliminary data for future in-depth studies to determine the molecular basis of obesity-dependent liver cancer.
肝癌是美国与癌症相关死亡的原因最快的原因之一, 全世界。由于肝癌,全球大约有700,000人死亡。风险因素 对于肝癌,包括非酒精性脂肪肝病,糖尿病和肥胖症以及发病率上升 这些疾病与肝癌的发病率越来越多。肝细胞的发展 癌症是肝癌的主要亚型,是一个多步过程,通常从慢性开始 炎。然而,炎症的分子和细胞原因仍然很少了解。 NOD2是细菌先天免疫蛋白,NOD2缺乏症与炎症有关 疾病,饮食诱导的肥胖和代谢功能障碍以及肥胖依赖性肝癌。初步的 数据,使用小鼠模型用于肝细胞癌,可以预测肝脏的发展 NOD2缺陷小鼠高脂肪饮食(HFD)的肿瘤发生与抑制AMP- 依赖激酶(AMPK)途径。 AMPK是代谢重编程和细胞的主调节器 增殖。但是,AMPK途径在NOD2缺陷小鼠中的作用尚未 被证明了。 在当前项目中,nod2 - / - 中AMPK途径激活降低的假设 肿瘤小鼠将测试这些小鼠的肝肿瘤发展。目标 1,将确定NOD2在AMPK途径激活中的作用。 WT和NOD2 - / - 小鼠将是 用致癌二甲基苯子[A]蒽(DMBA)处理,并在HFD(DMBA+HFD)上维持到 将在肝脏中确定诱导肝肿瘤和AMPK途径中蛋白质的调节。在AIM 2中, AMPK途径在NOD2 - / - 小鼠中肥胖依赖性肝肿瘤发展中的作用将是 决定。 NOD2 - / - DMBA+HFD小鼠将用二甲双胍治疗以激活AMPK并监测为 肝肿瘤的发展。这些实验的结果将提供概念概念的作用 NOD2在激活AMPK途径以及该途径在保护中的作用中的作用 肝细胞癌将为未来的深入研究提供初步数据,以确定 肥胖依赖性肝癌的分子基础。

项目成果

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Dipika Gupta其他文献

Dipika Gupta的其他文献

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{{ truncateString('Dipika Gupta', 18)}}的其他基金

Role of Nod2 and AMP-kinase in obesity-associated liver cancer
Nod2 和 AMP 激酶在肥胖相关肝癌中的作用
  • 批准号:
    10687174
  • 财政年份:
    2022
  • 资助金额:
    $ 7.93万
  • 项目类别:

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