Hepatic Rap1a in cholesterol homeostasis
肝脏 Rap1a 在胆固醇稳态中的作用
基本信息
- 批准号:10736498
- 负责人:
- 金额:$ 64.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAntibodiesArterial Fatty StreakAtherosclerosisAttenuatedBackBindingBiochemicalCETP geneCardiometabolic DiseaseCardiovascular DiseasesCause of DeathCholesterolCholesterol HomeostasisClinicDataDevelopmentDiabetic mouseDoseDrug PrescriptionsEpidemicEtiologyEventGlucagon ReceptorGlucose IntoleranceGoalsHealthcare SystemsHepaticHepatocyteHumanHyperlipidemiaInsulin ResistanceKnockout MiceLDL Cholesterol LipoproteinsLaboratoriesLesionLinkLiverLow Density Lipoprotein ReceptorLow-Density LipoproteinsMediatingMessenger RNAModelingMolecularMonomeric GTP-Binding ProteinsMusNon-Insulin-Dependent Diabetes MellitusObesityPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPhysiologicalPhysiologyPlasmaPost-Transcriptional RegulationPreventionProprotein Convertase 1Proprotein ConvertasesProteinsProteomicsRAS Superfamily ProteinsRegulationReportingResidual stateRoleSerumSocietiesSpecificitySubtilisinsTestingTherapeuticWorkapolipoprotein E-3blood glucose regulationcardiovascular disorder riskcardiovascular disorder therapygain of functiongeranylgeranyl pyrophosphategeranylgeranylationglucose productionimprovedin vivoinhibitorinsightisoprenoidmouse geneticsmouse modelmutantnew therapeutic targetnovelpharmacologicpleiotropismprenylationpreservationpreventrestorationsmall moleculetargeted treatmenttherapeutic target
项目摘要
PROJECT SUMMARY
Title: Hepatic Rap1a in cholesterol homeostasis
Atherosclerotic cardiovascular disease is the leading cause of death worldwide and lowering of proatherogenic
low-density lipoprotein (LDL) cholesterol (LDL-C) levels is the primary target of therapy. Recent work has
identified proprotein convertase subtilisin/ kexin type 9 (PCSK9) as a promising therapeutic target that regulates
serum LDL-C. Despite its critical role as a regulator of the LDL receptor (LDLR) and attractiveness as a
pharmacological target, the mechanism(s) by which PCSK9 is regulated remain largely unknown. Interestingly,
the most widely prescribed drugs for lowering plasma cholesterol, statins, dose-dependently increase PCSK9
levels, which largely negate further statin-induced increases in hepatic LDLR and attenuate their efficacy.
However, our understanding of the underlying cellular and molecular mechanisms of this regulation remains
incomplete. This proposal is based on a new finding from our laboratory suggesting that activation of the small
G protein of the Ras superfamily, Rap1a, lowers PCSK9 and plasma LDL-C levels. Further, Rap1a
geranylgeranyl prenylation and activity is inhibited in statin-treated hepatocytes and human liver, and restoring
intracellular geranylgeranyl isoprenoid levels prevents statin-induced PCSK9 and further lowers LDL-C. We
propose that hepatic Rap1a is a novel regulator of PCSK9 protein, and its inhibition via lower intracellular
isoprenoid levels may provide an additional mechanism to explain how statins increase PCSK9. Based on these,
we will define the mechanisms by which Rap1a regulates PCSK9 and LDL-C metabolism (Aim 1), elucidate it’s
in role statin-mediated PCSK9 induction (Aim 2), and explore the effect of combined statin and Rap1a activation
in the prevention of atherosclerotic lesion development. (Aim 3). We will test these new ideas in vivo and ex vivo,
using a combination of mouse genetic, physiological, and biochemical approaches.
项目摘要
标题:胆固醇稳态的肝RAP1A
动脉粥样硬化心血管疾病是全世界死亡的主要原因,降低了促孕育病
低密度脂蛋白(LDL)胆固醇(LDL-C)水平是治疗的主要靶标。最近的工作有
鉴定的提谋蛋白转化酶枯草蛋白/ Kexin类型9(PCSK9)是调节的有前途的治疗靶标
血清LDL-C。尽管它是LDL接收器(LDLR)的调节剂的关键作用,并且具有吸引力
药理学靶标,PCSK9受调节的机制在很大程度上尚不清楚。有趣的是,
降低血浆胆固醇,他汀类药物,剂量依赖性pcsk9的最广泛规定的药物
水平在很大程度上否定了他汀类药物诱导的肝脏LDLR的升高并降低其效率。
但是,我们对这种调节的潜在细胞和分子机制的理解仍然存在
不完整。该提议是基于我们实验室的新发现,表明激活小型
RAS超家族的G蛋白Rap1a,降低PCSK9和等离子体LDL-C水平。此外,Rap1a
汀类药物治疗的肝细胞和人肝脏中抑制黄烷基凝集丙酰基化和活性,并恢复
细胞内黄烷基类异丙基水平可防止他汀类药物诱导的PCSK9,并进一步降低LDL-C。我们
提议肝癌是PCSK9蛋白的新型调节剂,并且通过较低的细胞内抑制作用
类异型水平可能提供了一种额外的机制来解释他汀类药物如何增加PCSK9。基于这些,
我们将定义RAP1A调节PCSK9和LDL-C代谢的机制(AIM 1),阐明了它
在角色汀类药物介导的PCSK9诱导中(AIM 2),并探讨了他汀类药物和RAP1A激活的效果
在预防动脉粥样硬化病变的过程中。 (目标3)。我们将在Vivo和Ex Vivo中测试这些新想法,
结合小鼠遗传,物理和生化方法。
项目成果
期刊论文数量(1)
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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{{ truncateString('Lale Ozcan', 18)}}的其他基金
Role of Dach1 in Obesity-Induced Hepatic Insulin Resistance
Dach1 在肥胖引起的肝胰岛素抵抗中的作用
- 批准号:
9316590 - 财政年份:2016
- 资助金额:
$ 64.58万 - 项目类别:
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