Deep Phenotyping of Human Knockouts and Population Studies of the APOC3 Pathway
人类基因敲除的深度表型分析和 APOC3 通路的群体研究
基本信息
- 批准号:9902507
- 负责人:
- 金额:$ 67.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnkleApolipoprotein A-IApolipoproteins BApolipoproteins CAtherosclerosisBiologicalBiological MarkersBiologyCatabolismCellsCholesterolConsanguinityCoronary heart diseaseDataDiseaseDoseEventFatty acid glycerol estersFunctional disorderGenesGeneticGenotypeGlucoseHeparinHepaticHepatocyteHeterozygoteHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHigh PrevalenceHomeostasisHomozygoteHumanIndividualInflammationInflammatoryInsulinInsulin ResistanceIsotopesKineticsKnock-outKnowledgeLabelLipaseLipidsLipolysisLipoprotein (a)LipoproteinsLiver Function TestsLoss of HeterozygosityLow-Density LipoproteinsMeasuresMediatingMediationMetabolicMetabolic Clearance RateMetabolic DiseasesMetabolic PathwayMetabolismModelingMutationNon-Insulin-Dependent Diabetes MellitusOGTTOralParticipantPathway interactionsPatientsPhenotypePhysiologyPlasmaPopulationPopulation StudyProductionProteinsRiskRisk FactorsRoleSafetySubgroupTestingTherapeuticThickThromboplastinTracerTriglyceridesUncertaintyVery low density lipoproteinX-Ray Computed Tomographyapolipoprotein C-IIIatherosclerosis riskcardiometabolismcardiovascular risk factorcohortextracellulargenomic locusglucose metabolismheart disease riskhuman modelindexinginduced pluripotent stem cellinsightlipid metabolismlipoprotein lipaseliver functionloss of functionloss of function mutationparticlerare variantrecruitresponsestable isotopetherapeutic targetuptake
项目摘要
Several recent studies indicate that loss of function (LoF) mutations in the apolipoprotein C-III (APOC3) gene offer
protection from coronary heart disease (CHD) risk, possibly by reducing circulating triglyceride-rich lipoproteins
(TRLs). Inhibition of the apoC-III pathway can provide an attractive therapeutic mechanism to lower CHD risk.
There are however many outstanding uncertainties that exist, including impact of apoC-III deficiency on (i)
lipoprotein kinetics; (ii) high density lipoprotein remodeling and functionality; (iii) non-lipid related pathways; (iv) the
mechanisms by which apoC-III inhibition may reduce CHD risk, (v) the relative contribution of different lipoprotein-
associated apoC-III levels on CHD; (vi) liver function and insulin resistance from a safety perspective.
In this application, we propose studies to address these gaps by leveraging natural human models of
apoC-III deficiency. We have identified the world’s first humans with homozygous APOC3 genetic deficiency who
are from an isolated Pakistani village with a high prevalence of consanguinity. Recruitment of all inhabitants in this
village (~5000 people) has already been completed; genotyping in a subset has already identified 113 APOC3
knockouts with complete apoC-III deficiency providing opportunities for detailed phenotyping.
Specifically, in AIM-1, we will conduct deep phenotyping studies in 113 human APOC3 knockouts (n = 113)
and in an equal number of heterozygotes and non-carriers to address the following: (i) role of apoC-III deficiency in
modulating protein and lipid composition of TRLs to impact the activity of extracellular lipases; (ii) effect of apoC-III
deficiency on subclasses of LDL; (iii) role of apoC-III in modulating Lp(a) levels and composition; and (iv)
contribution of apoC-III deficiency to modulation of HDL composition and function. We will also address the
consequences of genetic APOC3 deficiency on (iv) systemic lipid and glucose metabolism and a range of proteins
related to inflammation and other pathways (v) dose-response association with atherosclerosis.
In AIM-2, we will conduct lipoprotein kinetic studies using isotope tracers on 18 trios of APOC3 null
homozygotes, heterozygotes, and non-carriers to evaluate the impact of apoC-III deficiency on kinetics of apoB-
containing lipoproteins and production and clearance of HDL apoA-I. We will also generate human iPS cells from 5
APOC3 knockouts and 5 matched/related non-carriers and differentiate them into hepatocytes to evaluate (a)
VLDL apoB and TG production (b) TRL and LDL uptake and (c) SRB1 mediated HDL uptake.
In AIM-3, we will measure total plasma apoC-III and lipoprotein-associated (apoB lipoproteins, HDL, and
Lp[a]) apoC-III in 5,000 participants from the EPIC-Norfolk cohort (2,500 with incident CHD events). These studies
will enable assessment of: (i) disease mediation; (ii) CHD risk progressively adjusted for lipoprotein-associated
apoC-III levels and other factors; (iii) dose-response association; (iv) relevance of apoC-III in subgroups (e.g., by
T2D); (v) risk prediction beyond traditional CHD risk factors; and (vi) genetic loci associated with apoC-III levels.
最近的几项研究表明,载脂蛋白C-III(APOC 3)基因的功能丧失(LoF)突变提供了
预防冠心病(CHD)风险,可能通过减少循环中富含磷脂酰肌醇的脂蛋白
(TRLs)。抑制apoC-III通路可以提供降低CHD风险的有吸引力的治疗机制。
然而,存在许多突出的不确定性,包括载脂蛋白C-III缺乏对(i)
脂蛋白动力学;(ii)高密度脂蛋白重塑和功能性;(iii)非脂质相关途径;(iv)脂蛋白代谢。
apoC-III抑制可降低CHD风险的机制,(v)不同脂蛋白的相对贡献,
相关的apoC-III水平对CHD的影响;(vi)从安全性的角度来看,肝功能和胰岛素抵抗。
在这个应用中,我们提出了研究,以解决这些差距,利用自然的人类模型,
apoC-III缺乏。我们已经确定了世界上第一个纯合子APOC 3基因缺陷的人,
都来自巴基斯坦一个偏僻的村庄,那里有很多近亲。招募所有居民,
一个村庄(约5000人)的基因分型已经完成;一个子集的基因分型已经确定了113个APOC 3
完全apoC-III缺陷的敲除提供了详细表型分析的机会。
具体而言,在AIM-1中,我们将在113例人APOC 3敲除(n = 113)中进行深入的表型研究。
以及在相同数量的杂合子和非携带者中,以解决以下问题:(i)apoC-III缺乏在
调节TRL的蛋白质和脂质组成以影响细胞外脂肪酶的活性;(ii)apoC-III的作用
LDL亚类缺乏;(iii)apoC-III在调节Lp(a)水平和组成中的作用;和(iv)
apoC-III缺乏对HDL组成和功能调节的贡献。我们还将讨论
遗传性APOC 3缺乏对(iv)全身脂质和葡萄糖代谢以及一系列蛋白质的影响
与炎症和其他途径有关(v)与动脉粥样硬化的剂量反应相关性。
在AIM-2中,我们将使用同位素示踪剂对18个APOC 3缺失的三联体进行脂蛋白动力学研究。
纯合子、杂合子和非携带者,以评估apoC-III缺乏对apoB-
含有脂蛋白和HDL apoA-I的产生和清除。我们还将从5个细胞中产生人类iPS细胞。
APOC 3敲除和5个匹配/相关的非携带者,并将其分化为肝细胞以评价(a)
VLDL apo B和TG产生(B)TRL和LDL摄取和(c)SRB 1介导的HDL摄取。
在AIM-3中,我们将测量总血浆apoC-III和脂蛋白相关(apoB脂蛋白、HDL和
来自EPIC-Norfolk队列的5,000名参与者(2,500名发生CHD事件)中的Lp[a])apoC-III。这些研究
将能够评估:(i)疾病调解;(ii)CHD风险逐步调整为脂蛋白相关
apoC-III水平和其他因素;(iii)剂量-反应相关性;(iv)亚组中apoC-III的相关性(例如,通过
T2 D);(v)传统CHD风险因素以外的风险预测;和(vi)与apoC-III水平相关的遗传基因座。
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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Daniel James Rader其他文献
Daniel James Rader的其他文献
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{{ truncateString('Daniel James Rader', 18)}}的其他基金
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