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.
在美国和欧洲,肝癌是癌症相关死亡增长最快的原因之一
项目成果
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Dipika Gupta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: