Effects of Genetic ANGPTL3 Deficiency on Hepatic Lipid Regulation and Lipoprotein Production
遗传性 ANGPTL3 缺陷对肝脏脂质调节和脂蛋白产生的影响
基本信息
- 批准号:10605624
- 负责人:
- 金额:$ 3.36万
- 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:2023-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAllelesAngiopoietinsApolipoproteins BCRISPR/Cas technologyCardiovascular DiseasesCause of DeathCell Culture SystemCell Culture TechniquesCell secretionCellsCharacteristicsChemicalsCholesterolCholesterol HomeostasisCirculationClinicalClinical TrialsCoronary ArteriosclerosisCulture MediaDataDiagnosisDyslipidemiasElementsFDA approvedFamilial HypercholesterolemiaFellowshipFollow-Up StudiesFutureGenesGeneticGoalsHepG2HepaticHepatocyteHomeostasisHumanHyperlipidemiaImpairmentKineticsKnock-outKnowledgeLDL Cholesterol LipoproteinsLabelLipaseLipidsLipolysisLipoproteinsLiverLoss of HeterozygosityMass Spectrum AnalysisMeasuresMetabolismModelingMolecularMonoclonal AntibodiesNational Heart, Lung, and Blood InstituteParticipantParticle SizePathway interactionsPatientsPeripheralPharmaceutical PreparationsPhenotypePhysiologic pulsePlasmaPlayPluripotent Stem CellsPopulationProductionProtein SecretionProteinsPublishingRadiolabeledReagentRecommendationRefractoryRegulationResearchResearch PersonnelResearch PriorityResourcesRiskRisk FactorsRoleStrategic PlanningSystemTestingTherapeuticTrainingTriglyceridesVariantVery low density lipoproteinWorkblood lipoproteincancer cellcardioprotectioncardiovascular risk factorcollaborative environmentderepressiondisorder riskdrug developmentearly onsetexperimental studygenome editinghuman monoclonal antibodieshuman stem cellshuman subjecthypolipidemiaimprovedinduced pluripotent stem cellinhibiting antibodyinsightion mobilitylipid metabolismlipidomicsloss of functionnew therapeutic targetnovelparticlepharmacologicpreventreceptorreceptor functionreuptakestem cell differentiationtherapeutic targettranscriptome sequencingtreatment responseuptake
项目摘要
ABSTRACT. Cardiovascular disease is the leading cause of death worldwide. A major goal of pharmacologic
therapy is to lower plasma lipids, especially low-density lipoprotein cholesterol (LDL), the cardinal risk factor for
coronary artery disease (CAD). Patients with familial hypercholesterolemia (FH) have increased risk of
developing early-onset CAD due to dysfunctional clearance of LDL from circulation and increased plasma levels
of this atherogenic lipoprotein. Underdiagnosis and undertreatment of FH are exacerbated by limited therapeutic
options. However, one strategy has been successful at lowering LDL in FH patients: Inhibition of the hepatically
secreted protein Angiopoietin-like protein 3 (ANGPTL3). A monoclonal antibody (evinacumab) inhibiting
circulating ANGPTL3 recently obtained FDA approval for treatment of FH due to substantial reductions in LDL,
even in patients with complete deficiency of the LDL receptor (LDLR). In contrast, existing lipid-lowering agents
largely rely on LDLR function to remove this atherogenic lipoprotein from the blood. In accordance with the
NHLBI Research Priorities, it is important for researchers to define molecular characteristics that can predict
meaningful or inadequate responses to therapy in different populations with cardiovascular disease. Despite
promising clinical trial data, the LDLR-independent mechanisms by which ANGPTL3 inhibition lowers LDL have
not been fully characterized. This is an important question to address not only to describe how drugs inhibiting
ANGPTL3 work but also to recommend targets for reducing plasma lipids via a novel LDLR-independent pathway
of lipoprotein metabolism. The main hypothesis of this proposal is that ANGPTL3 deficiency lowers LDL in part
by modulating hepatic lipoprotein assembly and lipid metabolism while simultaneously altering characteristics of
secreted VLDL particles. This hypothesis will be addressed by achieving the goals outlined in this proposal. The
proposed experiments employ a combination of hepatocyte cell culture systems, including immortalized cancer
cells and an advanced cell culture model that produces hepatocyte-like cells (HLCs) from induced pluripotent
stem cells (iPSCs). These iPSCs are derived from a unique population of human subjects with complete genetic
ANGPTL3 deficiency. Aim 1 will use these models to test whether changes in lipoprotein secretory transit and/or
lipid metabolism contribute to LDL lowering in ANGPTL3 deficiency. Aim 2 will test whether lipoprotein particle
secretion kinetics, clearance, size, and/or lipid composition could also be contributing to LDL lowering. These
experiments will be carried out as part of a rigorous fellowship training plan in a well-resourced and highly
collaborative environment. Consistent with the NHLBI Strategic Plan, the proposed studies will help future
clinician-investigators and the patients they serve by improving understanding of the functions of ANGPTL3-
inhibiting drugs; describing a role for ANGPTL3 in hepatic lipoprotein metabolism; and potentially recommending
new therapeutic targets for lipid-lowering agents by elucidating an LDLR-independent mechanism for clearance
of circulating LDL.
抽象的。心血管疾病是全世界死亡的主要原因。药理学的主要目标
治疗的目的是降低血浆脂质,尤其是低密度脂蛋白胆固醇(LDL),它是糖尿病的主要危险因素
冠状动脉疾病(CAD)。家族性高胆固醇血症(FH)患者罹患以下疾病的风险增加
由于循环中 LDL 清除功能障碍和血浆水平升高而导致早发 CAD
这种致动脉粥样硬化脂蛋白。有限的治疗措施加剧了 FH 的诊断不足和治疗不足
选项。然而,一种策略已成功降低 FH 患者的 LDL:抑制肝功能
分泌蛋白血管生成素样蛋白3 (ANGPTL3)。单克隆抗体(evinacumab)抑制
由于 LDL 大幅降低,循环中的 ANGPTL3 最近获得 FDA 批准用于治疗 FH,
即使是 LDL 受体 (LDLR) 完全缺乏的患者。相比之下,现有的降脂药
很大程度上依靠 LDLR 功能从血液中清除这种致动脉粥样硬化脂蛋白。根据
NHLBI 研究重点,研究人员定义可以预测的分子特征非常重要
不同心血管疾病人群对治疗的有意义或不充分的反应。尽管
有希望的临床试验数据表明,ANGPTL3 抑制可降低 LDL 的不依赖于 LDLR 的机制
尚未得到充分表征。这是一个需要解决的重要问题,不仅是为了描述药物如何抑制
ANGPTL3 不仅发挥作用,还通过一种新的 LDLR 独立途径推荐降低血浆脂质的目标
脂蛋白代谢。该提案的主要假设是 ANGPTL3 缺陷会部分降低 LDL
通过调节肝脂蛋白组装和脂质代谢,同时改变
分泌VLDL颗粒。这一假设将通过实现本提案中概述的目标来解决。这
拟议的实验采用肝细胞细胞培养系统的组合,包括永生化癌症
细胞和先进的细胞培养模型,可从诱导多能细胞中产生肝细胞样细胞 (HLC)
干细胞(iPSC)。这些 iPSC 源自具有完整遗传基因的独特人类受试者群体
ANGPTL3 缺陷。目标 1 将使用这些模型来测试脂蛋白分泌转运和/或
ANGPTL3 缺乏时脂质代谢有助于降低 LDL。目标2将测试脂蛋白颗粒是否
分泌动力学、清除率、大小和/或脂质成分也可能有助于降低 LDL。这些
实验将作为严格的奖学金培训计划的一部分在资源充足且高度发达的环境中进行。
协作环境。与 NHLBI 战略计划一致,拟议的研究将有助于未来
通过提高对 ANGPTL3 功能的理解,临床医生、研究人员及其所服务的患者
抑制药物;描述 ANGPTL3 在肝脂蛋白代谢中的作用;并可能推荐
通过阐明不依赖 LDLR 的清除机制,找到降脂药物的新治疗靶点
循环低密度脂蛋白。
项目成果
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Kendall Helene Burks的其他文献
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