Hepatic TGFbeta1 in Control of Type 2 Diabetes and NASH via FoxO1 Signaling
肝脏 TGFbeta1 通过 FoxO1 信号传导控制 2 型糖尿病和 NASH
基本信息
- 批准号:10532783
- 负责人:
- 金额:$ 51.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AlanineAlcohol abuseAmino AcidsApoptosisAspartateBindingBioinformaticsBiologyBloodBone MarrowCell SeparationCell physiologyChargeChemicalsClinicalCyclic AMPCyclic AMP-Dependent Protein KinasesCytoplasmDataDiabetes MellitusDietDiseaseDisease modelExtracellular MatrixExtracellular Matrix ProteinsFOXO1A geneFibrosisGene ExpressionGenesGeneticGenetic ModelsGenomicsGlucagonGluconeogenesisGrantHepaticHepatic Stellate CellHepatocyteHigh Fat DietHomeostasisHumanHyperglycemiaIRS1 geneIn VitroInflammationInsulinInsulin ReceptorInsulin ResistanceKnock-inKnockout MiceLipidsLiverLiver FailureLiver FibrosisLiver diseasesMacrophageMetabolicMetabolic stressMolecularMorbidity - disease rateMusMutant Strains MiceMutationNon-Insulin-Dependent Diabetes MellitusNuclearNuclear ExportNuclear ProteinNuclear TranslocationOvernutritionPIK3CG genePathway interactionsPhosphorylationPlayPreventionProteinsProto-Oncogene Proteins c-aktPublic HealthResearchRisk FactorsRoleSerineShapesSignal PathwaySignal TransductionSiteSteatohepatitisSystemTGFB1 geneTestingTherapeuticTissuesTransforming Growth Factor betaTransforming Growth FactorsUbiquitinationVirus Diseasesantagonistautocrinechronic liver injurycytokineeffective therapyfeedingforkhead proteingenetic approachgenomic locusgenomic toolsglucose metabolismglucose productionhigh riskinhibitorinsightinsulin signalinglipid biosynthesisliver functionliver inflammationmembernon-alcoholicnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnoveloverexpressionparacrinepharmacologicprogramsprotein expressionreceptorresponsesingle-cell RNA sequencingtranscription factortranscriptometranscriptome sequencing
项目摘要
Project Summary
Overnutrition induces insulin resistance, which is a high-risk factor for T2D and NASH. The
mechanism underlying insulin resistance-induced hepatic lipogenesis, fibrosis, apoptosis, and inflammation
for NASH is unclear. High levels of transforming growth factor-β1 (TGFβ1) in blood and tissues were
observed in both human and mice with T2D and NASH. TGF-β1 plays a pivotal role in a diverse range of
cellular responses, including extracellular matrix (ECM) synthesis and apoptosis which are essential for
tissue homeostasis, but the molecular mechanism by which TGFβ1 regulates glucose metabolism and liver
function is incompletely understood.
The forkhead transcription factor Foxo1 is a key downstream target of the insulin→ PI3K→protein
kinase B (Akt) signaling pathway and the glucagon→cAMP→protein kinase A (PKA) signaling pathway. Akt
phosphorylates Foxo1-Ser253, triggering Foxo1 nuclear export and cytoplasmic sequestration for
ubiquitination. By contrast, PKA phosphorylates Foxo1-Ser273 to promote Foxo1 nuclear translocation and
protein stability in hepatocytes. Upon metabolic stress such as overnutrition, Foxo1 hyperactivation
promotes hepatic glucose production (HGP) and hyperglycemia. In this proposal, the PI hypothesizes that
hepatic TGFβ1 plays key role in control of Foxo1 via phosphorylation at S273 (Foxo1-pS273), enhancing
Foxo1 nuclear activity, and inducing hyperglycemia, liver fibrosis and inflammation, and promoting T2D and
NASH. In Aim 1, PI and his team will use genetic approaches to 1) delete the TGFβ1 gene in the liver of
mice (L-TGFβ1KO) with or without active Foxo1-S273D/D mutation, or 2) generate liver-specific
overexpression TGFβ1 mice (L-TGFβ1OE) with or without inactive Foxo1-S273A/A mutation, investigating
whether hepatic TGFβ1 is a key controller for Foxo1-pS273 in promoting HGP, apoptosis, liver fibrosis and
inflammation following the NASH diet feeding. Aim2 is to use mouse primary hepatocytes, bone marrow-
derived macrophages, and hepatic stellate cells (HSC) to determine the mechanisms by which TGFβ1
promotes macrophage depolarization and HSC activation via Foxo1-pS273 in hepatocytes. The specific-
domain interactions of Smad3 and Foxo1 and related target genes expression in hepatocytes will be further
investigated. Aim 3 is to investigate whether suppression of systematic or hepatic TGFβ1 signaling is
sufficient for the prevention of T2D and NASH in mice, in a Foxo1 dependent manner. Overall, using the
genetic, genomic, bioinformatic, and pharmacological approaches, the PI and his team are fully equipped to
investigate the new pathophysiological role of hepatic TGF-β1→Foxo1-pS273→TGFβ1 looping system in
control of T2D and NASH, which will provide novel insights on mechanism of diabetes and NASH.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Shaodong Guo其他文献
Research on the Comprehensive Benefit Evaluation of Electric Vehicle Technology Promotion and Application Under the Strategic Background of “Carbon Peaking and Carbon Neutrality”
- DOI:
10.1007/s42835-023-01643-4 - 发表时间:
2023-09-14 - 期刊:
- 影响因子:1.600
- 作者:
Dexiang Jia;Xinda Li;Shaodong Guo;Fang Liu;Chengcheng Fu;Xingde Huang;Zhen Dong;Jing Liu - 通讯作者:
Jing Liu
Shaodong Guo的其他文献
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{{ truncateString('Shaodong Guo', 18)}}的其他基金
Hepatic TGFbeta1 in Control of Type 2 Diabetes and NASH via FoxO1 Signaling
肝脏 TGFbeta1 通过 FoxO1 信号传导控制 2 型糖尿病和 NASH
- 批准号:
10365367 - 财政年份:2021
- 资助金额:
$ 51.34万 - 项目类别:
Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus
通过雌激素受体靶向胰岛素抵抗来控制 2 型糖尿病
- 批准号:
10018033 - 财政年份:2019
- 资助金额:
$ 51.34万 - 项目类别:
Targeting Insulin Resistance by Estrogen Receptor in Control of Type 2 Diabetes Mellitus
通过雌激素受体靶向胰岛素抵抗来控制 2 型糖尿病
- 批准号:
10407999 - 财政年份:2019
- 资助金额:
$ 51.34万 - 项目类别:
Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling
FoxO 信号传导对代谢和肝脏稳态的转录调节
- 批准号:
8661768 - 财政年份:2012
- 资助金额:
$ 51.34万 - 项目类别:
Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling
FoxO 信号传导对代谢和肝脏稳态的转录调节
- 批准号:
8463523 - 财政年份:2012
- 资助金额:
$ 51.34万 - 项目类别:
Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling
FoxO 信号传导对代谢和肝脏稳态的转录调节
- 批准号:
8272104 - 财政年份:2012
- 资助金额:
$ 51.34万 - 项目类别:
Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling
FoxO 信号传导对代谢和肝脏稳态的转录调节
- 批准号:
9061672 - 财政年份:2012
- 资助金额:
$ 51.34万 - 项目类别:
Transcriptional Regulation of Metabolic and Hepatic Homeostasis by FoxO Signaling
FoxO 信号传导对代谢和肝脏稳态的转录调节
- 批准号:
9264906 - 财政年份:2012
- 资助金额:
$ 51.34万 - 项目类别:
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