A Glucocorticoid Receptor-SETDB2 Co-Regulated Liver Metabolic Gene Program
糖皮质激素受体-SETDB2协同调控肝脏代谢基因计划
基本信息
- 批准号:10112447
- 负责人:
- 金额:$ 53.19万
- 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:2021-01-08 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse effectsAffectAnti-Inflammatory AgentsAreaBindingCREB1 geneCardiovascular DiseasesCell NucleusChIP-seqChromatinChromatin LoopChronicClinicalCodeCollaborationsCytoplasmDNA receptorDataDevelopmentDexamethasoneDiabetes MellitusDiseaseEnhancersEnzymesEpigenetic ProcessEquilibriumExposure toFastingFatty LiverFatty acid glycerol estersGene ActivationGene ExpressionGene Expression RegulationGene TargetingGenesGenomeGenomicsGlucagonGlucocorticoid ReceptorGlucocorticoidsGluconeogenesisGlucoseGlucose IntoleranceHepaticHomeostasisHormonalHormonesHumanHyperglycemiaHyperlipidemiaInsulin ResistanceKnock-outKnowledgeLeadLipidsLiverLongitudinal StudiesMediatingMetabolicMetabolic DiseasesMetabolic dysfunctionMetabolic stressMetabolic syndromeMetabolismMolecularMusMuscular AtrophyNon-Insulin-Dependent Diabetes MellitusNutritionalObesityPathway interactionsPatientsPhysiologicalPlayPostabsorptive HypoglycemiaProteinsPublishingRegulationResearchResponse ElementsRisk FactorsRoleSET DomainSiteStressStudy modelsTransactivationUntranslated RNAVisceral fatWeight GainWeights and MeasuresWorkcell typechromatin modificationclinically relevantdiet-induced obesityepigenomicsexperimental studyfeedinggene repressiongenome-wideglucocorticoid receptor alphaglucose productionhuman diseasehypercholesterolemiaimmunoregulationinsightliver metabolismmouse genomemouse modelnew therapeutic targetnovelnovel therapeutic interventionpreventprogramspromoterreceptor functionrecruitresponseside effectsynergismtranscription factortranscriptome sequencing
项目摘要
Excess glucocorticoids contribute to the development of diabetes and metabolic syndrome, which includes: obesity, hyperglycemia, hypercholesterolemia, insulin resistance, and liver steatosis. Glucocorticoids exert their physiological effects via the glucocorticoid receptor (GR), a transcription factor that binds chromatin at GRE motifs leading to gene activation or repression. Our published work identified a previously unrecognized mechanism for GR-mediated gene regulation through its collaboration with the SET domain-containing protein, SETDB2, to activate a select subset of GR gene targets in the liver associated with diabetes. We showed livers of mice deficient in SETDB2 have a significantly blunted glucocorticoid response as demonstrated by fasting hypoglycemia and lack of induction of key GR target genes. Since inhibition of glucocorticoid action in liver can prevent the negative metabolic effects of glucocorticoid-induced diabetes, we hypothesize that liver-specific
SETDB2-knockout (DB2-LKO) mice will be partially protected from metabolic dysfunction when exposed to conditions that lead to elevated glucocorticoids. Fundamental mechanisms associated with glucocorticoid-induced metabolic disease are studied by evaluating the effects of liver-specific DB2-LKO and liver-specific GR-LKO on glucose/lipid homeostasis under conditions of elevated endogenous glucocorticoids (diet- induced obesity) or exogenous glucocorticoid administration. Metabolic parameters associated with diabetes will be measured: weight gain, glucose-intolerance, insulin-resistance, hyperlipidemia, and hepatic steatosis. Additionally, the molecular mechanism for the combined action of SETDB2 and GR will be characterized within these experimental paradigms and novel gene targets and chromatin targeting will be identified by RNA-seq, ChIP-seq and Hi-ChIP. Integrating the proposed experiments will provide a better understanding of how SETDB2 affects the positive and negative actions of GR that are relevant to metabolic disease in the liver. The
fundamental mechanism studied may provide a pathway to target SETDB2’s role in GR action as a new
therapeutic target for glucocorticoid-induced diabetes and metabolic disease. The experiments a balance of mechanistic and exploratory studies in mouse models to investigate the regulation of hepatic metabolic processes that are directly relevant to human disease. The results from both aims will be integrated together to reveal the overlapping and unique mechanisms by which the SETDB2-GR regulatory axis contributes to the adaptation of the liver to acute nutritional (Aim 1), chronic nutritional and hormonal (Aim 2) states of metabolic stress.
过量的糖皮质激素有助于糖尿病和代谢综合征的发展,其中包括:肥胖、高血糖、高胆固醇血症、胰岛素抵抗和肝脂肪变性。糖皮质激素通过糖皮质激素受体(GR)发挥其生理作用,GR是一种转录因子,在GRE基序上结合染色质,导致基因激活或抑制。我们发表的研究发现了一种以前未被认识到的GR介导的基因调控机制,通过它与含有SET结构域的蛋白SETDB2合作,激活肝脏中与糖尿病相关的GR基因靶点的选择子集。我们发现,缺乏SETDB2的小鼠肝脏糖皮质激素反应明显减弱,这可以通过空腹低血糖和缺乏关键GR靶基因的诱导来证明。由于抑制糖皮质激素在肝脏中的作用可以防止糖皮质激素诱导的糖尿病的负代谢影响,我们假设肝脏特异性
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)
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Timothy F Osborne其他文献
Timothy F Osborne的其他文献
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{{ truncateString('Timothy F Osborne', 18)}}的其他基金
A Glucocorticoid Receptor-SETDB2 Co-Regulated Liver Metabolic Gene Program
糖皮质激素受体-SETDB2协同调控肝脏代谢基因计划
- 批准号:
10326407 - 财政年份:2021
- 资助金额:
$ 53.19万 - 项目类别:
A Glucocorticoid Receptor-SETDB2 Co-Regulated Liver Metabolic Gene Program
糖皮质激素受体-SETDB2协同调控肝脏代谢基因计划
- 批准号:
10534202 - 财政年份:2021
- 资助金额:
$ 53.19万 - 项目类别:
Epigenetic regulation of adipose tissue distribution in women
女性脂肪组织分布的表观遗传调控
- 批准号:
9306064 - 财政年份:2016
- 资助金额:
$ 53.19万 - 项目类别:
Physiology and regulation of T2R bitter taste receptors in enteroendocrine cells
肠内分泌细胞T2R苦味受体的生理学和调节
- 批准号:
8820259 - 财政年份:2013
- 资助金额:
$ 53.19万 - 项目类别:
Physiology and regulation of T2R bitter taste receptors in enteroendocrine cells
肠内分泌细胞T2R苦味受体的生理学和调节
- 批准号:
8528267 - 财政年份:2013
- 资助金额:
$ 53.19万 - 项目类别:
Physiology and regulation of T2R bitter taste receptors in enteroendocrine cells
肠内分泌细胞T2R苦味受体的生理学和调节
- 批准号:
8626394 - 财政年份:2013
- 资助金额:
$ 53.19万 - 项目类别:
Physiology and regulation of T2R bitter taste receptors in enteroendocrine cells
肠内分泌细胞T2R苦味受体的生理学和调节
- 批准号:
9025778 - 财政年份:2013
- 资助金额:
$ 53.19万 - 项目类别:
Integrated Regulation of Bile Acids and Diabetes
胆汁酸与糖尿病的综合调节
- 批准号:
8152616 - 财政年份:2010
- 资助金额:
$ 53.19万 - 项目类别:
Integrated Regulation of Bile Acids and Diabetes
胆汁酸与糖尿病的综合调节
- 批准号:
7225821 - 财政年份:2006
- 资助金额:
$ 53.19万 - 项目类别:
Integrated Regulation of Bile Acids and Diabetes
胆汁酸与糖尿病的综合调节
- 批准号:
7393086 - 财政年份:2005
- 资助金额:
$ 53.19万 - 项目类别:
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