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

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)
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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

Undiagnosed diseases network clinical site
未确诊疾病网络临床网站
  • 批准号:
    10600336
  • 财政年份:
    2022
  • 资助金额:
    $ 67.9万
  • 项目类别:
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:
Undiagnosed diseases network clinical site
未确诊疾病网络临床网站
  • 批准号:
    10266763
  • 财政年份:
    2018
  • 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:

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