Hepatic Wnt/LRP6 Regulation of Plasma Lipids
肝脏 Wnt/LRP6 对血浆脂质的调节
基本信息
- 批准号:9174908
- 负责人:
- 金额:$ 21.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-11-19 至 2016-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelApolipoproteins BAtherosclerosisCardiovascular DiseasesCellsCholesterolClinical ResearchCombined Modality TherapyCoronary ArteriosclerosisCoronary arteryCrossbreedingDevelopmentDiabetes MellitusDietDiseaseDisease PathwayDrug TargetingExhibitsFRAP1 geneFamilial Combined HyperlipidemiaFatty LiverFunctional disorderGeneral PopulationGenesGenetic Predisposition to DiseaseGenetic studyHepaticHepatocyteHeterozygoteHomeostasisHomozygoteHumanHyperlipidemiaIGF1 geneIGF1R geneImpairmentIndividualInsulinInvestigationKnock-outKnockout MiceLDL Cholesterol LipoproteinsLinkLipidsLipoproteinsLiverLiver diseasesLow-Density LipoproteinsMediator of activation proteinMetabolic syndromeModelingMolecularMusMutationNon-Insulin-Dependent Diabetes MellitusOnline Mendelian Inheritance In ManPathway interactionsPhenotypePhosphorylationPlasmaPoint MutationProteinsProto-Oncogene Proteins c-aktRegulationRiskRisk FactorsRoleScienceTCF7L2 geneTherapeutic AgentsTriglyceridesVariantVery low density lipoproteinWNT Signaling PathwayWnt proteinsbeta cateninbiological systemsearly onsetgenetic varianthuman diseaseinsulin signalinglipid biosynthesislipid disorderloss of function mutationlow density lipoprotein triglyceridemetabolic phenotypemouse modelnew therapeutic targetnovelnovel therapeuticsoverexpressionpreventpublic health relevancetherapeutic developmenttranscription factor
项目摘要
DESCRIPTION (provided by applicant): The genetic etiology and the molecular mechanisms of combined hyperlipidemia (CHL), the most common lipid disorder of the general population is not understood. Accordingly, no single therapeutic agent is available that completely normalizes both plasma LDL and TG, and or prevent cardiovascular disease. We have identified rare loss of function mutations in Wnt coreceptor LRP6 that underlie early atherosclerosis, and metabolic phenotypes including CHL. Since our initial discovery altered plasma levels and or functions of Wnt proteins and LRP6 antagonists have been associated with risk of hyperlipidemia and early onset CAD in the general population. In addition, common variants in Wnt transcription factor TCF7L2 have been associated with familial CHL. These findings have implicated Wnt signaling in hyperlipidemia and early onset atherosclerosis. To investigate disease mechanisms, mice with the human LRP6R611C (LRP6mut/mut) point mutation were generated. LRP6mut/mut mice exhibit significantly elevated plasma triglycerides (TG) and LDL cholesterols on high cholesterol diet, which dramatically increases after they are crossbred onto LDLR/ mice. Further studies in these mice revealed enhanced expression of liver IGF1/IGF1R associated with augmented activities of AKT/mTOR pathways, leading to increased SREBP1 and 2 activation, lipid synthesis and ApoB secretion. Strikingly, these changes normalized and hyperlipidemia was rescued by systemic Wn3a administration. We have devised several mouse models and propose to study the role of canonical Wnt/ß-catenin/ TCF7L2, and their potential downstream pathways IGF1 and mTORC2 in regulation of lipid synthesis and ApoB secretion. These studies hold great promise for identifying novel pathways and potential targets for development of therapeutics against combined hyperlipidemia.
描述(由适用提供):遗传病因和组合高脂血症(CHL)的分子机制,这是一般人群中最常见的脂质疾病。彼此之间,没有单一的治疗剂可完全使血浆LDL和TG完全归一化,并且可以预防心血管疾病。我们已经确定了在早期动脉粥样硬化和包括CHL在内的代谢表型的基础的Wnt共感受器LRP6中罕见的功能突变丧失。由于我们最初的发现改变了Wnt蛋白和LRP6拮抗剂的血浆水平和或功能与普通人群中高脂血症和早期发作CAD的风险有关。此外,Wnt转录因子TCF7L2中的常见变体与族CHL有关。这些发现已在高脂血症和早期发作动脉粥样硬化中实施了WNT信号传导。为了研究疾病机制,产生了具有人类LRP6R611C(LRP6MUT/MUT)点突变的小鼠。 LRP6MUT/ MUT小鼠暴露于高胆固醇饮食上的血浆甘油三酸酯(TG)和LDL胆固醇显着升高,在将它们杂交到LDLR/小鼠上后它们会急剧增加。在这些小鼠中的进一步研究表明,与AKT/MTOR途径增强活性相关的肝IGF1/IGF1R的表达增强,从而导致SREBP1和2激活增加,脂质合成和APOB分泌。令人惊讶的是,这些变化正常化,高脂血症由全身性WN3A给药做出了反应。我们设计了几种小鼠模型和建议,以研究规范Wnt/ß-catenin/ tcf7l2的作用,以及它们的潜在下游途径IGF1和MTORC2在调节脂质合成和APOB分泌方面的作用。这些研究具有识别新的途径和潜在靶标,用于开发针对联合高脂血症的疗法的潜在靶标。
项目成果
期刊论文数量(0)
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Arya Mani其他文献
Arya Mani的其他文献
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Genetic Regulation of Arterial Wall by Canonical Wnt Signaling
典型 Wnt 信号传导对动脉壁的遗传调控
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8674294 - 财政年份:2014
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Hepatic Wnt/LRP6 Regulation of Plasma Lipids
肝脏 Wnt/LRP6 对血浆脂质的调节
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$ 21.84万 - 项目类别:
Hepatic Wnt/LRP6 Regulation of Plasma Lipids
肝脏 Wnt/LRP6 对血浆脂质的调节
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8972032 - 财政年份:2014
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