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 (APOC3) 基因中的功能丧失 (LoF) 突变会导致
可能通过减少循环中富含甘油三酯的脂蛋白来预防冠心病 (CHD) 风险
(TRL)。抑制 apoC-III 通路可以提供一种有吸引力的治疗机制来降低 CHD 风险。
然而,存在许多突出的不确定性,包括 apoC-III 缺陷对 (i) 的影响
脂蛋白动力学; (ii) 高密度脂蛋白重塑和功能; (iii)非脂质相关途径; (四)
apoC-III 抑制可降低 CHD 风险的机制,(v) 不同脂蛋白的相对贡献
与 CHD 相关的 apoC-III 水平; (vi) 从安全角度看肝功能和胰岛素抵抗。
在此应用中,我们提出研究通过利用自然人类模型来解决这些差距
apoC-III 缺乏。我们发现了世界上第一例患有纯合 APOC3 遗传缺陷的人类
他们来自巴基斯坦一个偏僻的村庄,血缘关系盛行。招募本区所有居民
村庄(~5000人)已经建成;子集中的基因分型已鉴定出 113 个 APOC3
完全 apoC-III 缺陷的基因敲除为详细表型分析提供了机会。
具体来说,在 AIM-1 中,我们将对 113 个人类 APOC3 敲除(n = 113)进行深度表型研究
并在相同数量的杂合子和非携带者中解决以下问题:(i) apoC-III 缺陷在
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
低密度脂蛋白亚类缺乏; (iii) apoC-III 在调节 Lp(a) 水平和组成中的作用; (四)
apoC-III 缺乏对 HDL 组成和功能调节的贡献。我们还将解决
遗传性 APOC3 缺陷对 (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。
在 AIM-2 中,我们将使用同位素示踪剂对 18 个 APOC3 null 三重奏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 缺陷对 apoB- 动力学的影响
含有脂蛋白以及 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
APOC3 敲除和 5 个匹配/相关非携带者并将其分化为肝细胞以进行评估 (a)
VLDL apoB 和 TG 产生 (b) TRL 和 LDL 摄取以及 (c) SRB1 介导的 HDL 摄取。
在 AIM-3 中,我们将测量总血浆 apoC-III 和脂蛋白相关蛋白(apoB 脂蛋白、HDL 和
Lp[a]) apoC-III 是来自 EPIC-Norfolk 队列的 5,000 名参与者(其中 2,500 名发生了 CHD 事件)。这些研究
将能够评估:(i) 疾病调节; (ii) 根据脂蛋白相关因素逐步调整冠心病风险
apoC-III 水平和其他因素; (iii) 剂量-反应关联; (iv) apoC-III 在亚组中的相关性(例如,通过
T2D); (v) 超越传统冠心病风险因素的风险预测; (vi) 与 apoC-III 水平相关的遗传位点。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Daniel James Rader其他文献
Daniel James Rader的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
UDN@CHOP/UPENN:向可持续发展过渡
- 批准号:
10905924 - 财政年份:2018
- 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:
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:
相似国自然基金
ANKLE2通过调控PINK1减轻脓毒症心肌细胞线粒体钙超载的机制研究
- 批准号:CSTB2023NSCQ-MSX0603
- 批准年份:2023
- 资助金额:10.0 万元
- 项目类别:省市级项目
影响核膜与内质网膜结构的ANKLE2分子在衰老调控中的关键作用
- 批准号:91649107
- 批准年份:2016
- 资助金额:60.0 万元
- 项目类别:重大研究计划
相似海外基金
Assist-as-Needed Ankle Assistance Strategy Integrating Immersive MR system for Ensuring Voluntary Effort and Stimulating Neurorepair during Post-Stroke Gait Training
按需协助踝关节辅助策略集成沉浸式 MR 系统,确保中风后步态训练期间的自愿努力并刺激神经修复
- 批准号:
24K21161 - 财政年份:2024
- 资助金额:
$ 67.9万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Laboratory testing and development of a new adult ankle splint
新型成人踝关节夹板的实验室测试和开发
- 批准号:
10065645 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Collaborative R&D
Ankle-and-foot orthotic tailored for complex foot-ankle injury
针对复杂足踝损伤量身定制的踝足矫形器
- 批准号:
2895322 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Studentship
Collaborative Research: Bioinspired High Energy Recycling Mechanism Ankle Foot Prosthesis
合作研究:仿生高能回收机制踝足假肢
- 批准号:
2231031 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Standard Grant
Collaborative Research: Bioinspired High Energy Recycling Mechanism Ankle Foot Prosthesis
合作研究:仿生高能回收机制踝足假肢
- 批准号:
2231032 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Standard Grant
Morphologic and Kinematic Adaptations of the Subtalar Joint after Ankle Fusion Surgery in Patients with Varus-type Ankle Osteoarthritis
内翻型踝骨关节炎患者踝关节融合手术后距下关节的形态和运动学适应
- 批准号:
10725811 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Longitudinal Changes in Gait and Ankle Function in Youth with Charcot-Marie-Tooth Disease
患有腓骨肌萎缩症的青少年步态和踝关节功能的纵向变化
- 批准号:
10811149 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
EFFECTS OF DISEASE AND PALLIDAL DEEP BRAIN STIMULATION ON ANKLE MUSCLE CONTROL IN PARKINSON'S DISEASE
疾病和苍白球深部脑刺激对帕金森病患者踝关节肌肉控制的影响
- 批准号:
10749673 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Epidemiological Study and Pathophysiology of Ankle Sprain by Direct Examination of Junior High and High School Basketball Players
初高中篮球运动员踝关节扭伤的流行病学及病理生理学直接检查
- 批准号:
23K10615 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Collaborative Research: SCH: Improving Older Adults' Mobility and Gait Ability in Real-World Ambulation with a Smart Robotic Ankle-Foot Orthosis
合作研究:SCH:使用智能机器人踝足矫形器提高老年人在现实世界中的活动能力和步态能力
- 批准号:
2306660 - 财政年份:2023
- 资助金额:
$ 67.9万 - 项目类别:
Standard Grant