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.
肝癌是美国癌症相关死亡增长最快的原因之一, 国际吧全世界每年约有70万人死于肝癌。危险因素 肝癌的发病率包括非酒精性脂肪肝、糖尿病和肥胖, 这些疾病与肝癌的发病率增加有关。肝细胞癌的发展 肝癌是肝癌的主要亚型,是一个多步骤的过程,通常从慢性 炎症然而,炎症的分子和细胞原因仍然知之甚少。 Nod 2是一种细菌先天免疫蛋白,Nod 2缺乏与炎症相关。 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 使用小鼠肝细胞癌模型的数据预测, 在高脂饮食(HFD)的Nod 2缺陷小鼠中的肿瘤发生与AMP-1的抑制有关。 依赖性激酶(AMPK)途径。AMPK是代谢重编程和细胞凋亡的主要调节因子, 增殖然而,在Nod 2缺陷小鼠中AMPK通路在肝肿瘤发生中的作用还没有被证实。 被证明。 在目前的项目中,假设在Nod 2-/-中AMPK通路的激活减少, 将测试致瘤小鼠,其有助于这些小鼠中肝肿瘤的发展。在Aim中 1,将确定Nod 2在AMPK通路活化中的作用。WT和Nod 2-/-小鼠将在 用致癌物二甲基苯并[a]蒽(DMBA)处理并维持HFD(DMBA+HFD), 诱导肝肿瘤和AMPK途径中蛋白质的调节将在肝脏中确定。在目标2中, AMPK途径在Nod 2-/-小鼠肥胖依赖性肝肿瘤发生中的作用将被 测定Nod 2-/- DMBA+HFD小鼠将接受二甲双胍治疗以激活AMPK并监测其 肝肿瘤的发展。这些实验的结果将为以下作用提供概念验证: Nod 2在AMPK通路激活中的作用以及该通路在保护免于发展中的作用。 并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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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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