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
- 来源:
- 关键词:AddressAutophagocytosisBacteriaBindingBioinformaticsBody WeightCancer EtiologyCarcinogensCell LineCell ProliferationCell physiologyCessation of lifeChronicClinicalCrohn&aposs diseaseDataDevelopmentDiabetes MellitusDiseaseFutureGene ExpressionGenesGoalsHealthHepatocarcinogenesisHigh Fat DietHyperglycemiaHyperlipidemiaIncidenceIndividualInflammationInflammatoryInnate Immune ResponseInnate Immune SystemInsulin ResistanceLiverLiver neoplasmsMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of liverMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolismMetforminMethodsMissionMitochondriaMolecularMonitorMusMutationNatural ImmunityObesityObesity associated liver diseasePathway interactionsPattern recognition receptorPhosphotransferasesPredispositionPreventionPrimary carcinoma of the liver cellsPrincipal InvestigatorProcessProteinsPublic HealthPublishingRegulationResearchRisk FactorsRoleRole ConceptsSTK11 geneTestingUnited States National Institutes of Healthadenylate kinasebasebiological adaptation to stresscancer therapycolitis associated cancerdiet-induced obesitydifferential expressiondimethylbenzanthraceneexperimental studyfatty liver diseasehepatocellular carcinoma cell linein vivoknock-downlipid biosynthesisliver cancer modelliver developmentmicrobiotamouse modelnon-alcoholic fatty liver diseaseobese personobesity developmentobesity preventionobesity treatmentoverexpressionprogramsprotein activationpuptumorigenesistumorigenic
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.
在美国,肝癌是癌症相关死亡人数增长最快的原因之一
全世界。全球每年约有70万人死于肝癌。风险因素
包括非酒精性脂肪性肝病、糖尿病和肥胖症,以及
这些疾病与肝癌发病率的增加是平行的。肝细胞癌的研究进展
癌症是肝癌的主要亚型,是一个多步骤的过程,通常始于慢性
发炎。然而,炎症的分子和细胞原因仍然知之甚少。
NOD2是一种细菌天然免疫蛋白,NOD2缺乏与炎症有关
疾病,饮食引起的肥胖和代谢功能障碍,以及肥胖依赖型肝癌。初步
使用小鼠肝细胞癌模型的数据预测,肝脏的发育
高脂饮食(HFD)NOD2基因缺陷小鼠的肿瘤发生与抑制AMP-2有关
依赖激酶(AMPK)途径。AMPK是新陈代谢重新编程和细胞的主要调节器
扩散。然而,AMPK通路在NOD2缺陷小鼠肝脏肿瘤发生中的作用尚未见报道
已经被证明了。
在目前的项目中,假设在NOD2-/-中AMPK通路的激活减少
将对导致这些小鼠肝脏肿瘤发展的致瘤小鼠进行测试。在AIM
1,将确定NOD2在AMPK通路激活中的作用。WT和NOD2-/-小鼠将被
用致癌物二甲基苯并[a]菲(DMBA)处理,并在HFD(DMBA+HFD)上保持,以
诱导肝脏肿瘤和调节AMPK通路中的蛋白质将在肝脏中确定。在目标2中,
AMPK通路在肥胖依赖的NOD2/-小鼠肝肿瘤发展中的作用将是
下定决心。NOD2-/-DMBA+HFD小鼠将被二甲双胍激活AMPK并监测
肝脏肿瘤的发展。这些实验的结果将为以下角色提供概念证明
NOD2在AMPK通路的激活中的作用以及该通路在防止肿瘤发生发展中的作用
并将为未来的深入研究提供初步数据,以确定
肥胖依赖型肝癌的分子基础。
项目成果
期刊论文数量(0)
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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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