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.
最近的一些研究表明,载脂蛋白C-III (APOC3)基因的功能丧失(LoF)突变提供了一种新的治疗方法
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
Mechanisms by which ABCA7 activity influences Alzheimer's Disease
ABCA7 活性影响阿尔茨海默病的机制
- 批准号:
10525795 - 财政年份:2022
- 资助金额:
$ 67.9万 - 项目类别:
Deep Phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 Human Knockouts and Population Based Studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10186801 - 财政年份:2019
- 资助金额:
$ 67.9万 - 项目类别:
Deep phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 human knockouts and population based studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10528964 - 财政年份:2019
- 资助金额:
$ 67.9万 - 项目类别:
UDN@CHOP/UPENN: transition to sustainability
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10905924 - 财政年份:2018
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$ 67.9万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants
使用天然变体进行甘油三酯调节剂 ApoA-V 的结构功能分析
- 批准号:
10211481 - 财政年份:2016
- 资助金额:
$ 67.9万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulator ApoA-V Using Natural Variants
使用天然变体进行甘油三酯调节剂 ApoA-V 的结构功能分析
- 批准号:
10605242 - 财政年份:2016
- 资助金额:
$ 67.9万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulators ApoC-III and ApoA-V Using Natural Variants
使用天然变体对甘油三酯调节剂 ApoC-III 和 ApoA-V 进行结构-功能分析
- 批准号:
9306180 - 财政年份:2016
- 资助金额:
$ 67.9万 - 项目类别:
Structure-Function Analysis of Triglyceride Regulators ApoC-III and ApoA-V Using Natural Variants
使用天然变体对甘油三酯调节剂 ApoC-III 和 ApoA-V 进行结构-功能分析
- 批准号:
9158709 - 财政年份:2016
- 资助金额:
$ 67.9万 - 项目类别:
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