ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING

ORP6 在细胞内胆固醇贩运中的作用

基本信息

  • 批准号:
    RGPIN-2020-04851
  • 负责人:
  • 金额:
    $ 2.7万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2022
  • 资助国家:
    加拿大
  • 起止时间:
    2022-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Homeostasis, or the maintenance of a steady-state internal environment by living systems, is a core principal of life. Cholesterol homeostasis is a conserved and essential eukaryotic process. Within mammalian cells, intracellular membrane cholesterol levels are tightly regulated, with complex cellular mechanisms in place to maintain proper cholesterol concentrations at distinct intracellular sites. For this, both vesicular and non-vesicular cholesterol trafficking pathways are required for cholesterol movement between cell compartments. Despite extensive study of these pathways, many questions remain about the mechanisms of cholesterol transfer between different cell compartments and how these processes are regulated. Oxysterol-binding (OSBP)-related proteins (ORPs) are a family of lipid transfer proteins (LTPs) implicated in many cellular processes related with oxysterols, inter-organelle contact, lipid metabolism and non-vesicular sterol transport. The goal of my NSERC research program is to investigate the role of LTPs in the maintenance of cellular and whole-body cholesterol homeostasis. Oxysterol-binding protein-Related Protein 6 (ORP6), a poorly characterized member of the ORP family, has recently emerged as a novel regulator of intracellular cholesterol levels. We previously showed that ORP6 regulates cholesterol trafficking between cell compartments (endosomes and the ER) and the plasma membrane for efflux. Yet, how ORP6 regulates these pathways, and its function in the brain where it is most highly expressed, are unknown. Gene and protein expression data provide evidence that ORP6 expression is enriched in the brain relative to other tissues, and more specifically in astrocytes and neurons relative to other cells of the central nervous system (CNS). To investigate how ORP6 regulates cholesterol transport and to define its physiological role in whole-body cholesterol homeostasis, we propose to: I.Investigate the role of ORP6 in neuronal and glial cholesterol homeostasis. II.Identify mechanisms of ORP6-mediated cholesterol trafficking. III.Determine the physiological role of ORP6 in cholesterol homeostasis. The current proposal combines my unique expertise on oxysterol-binding proteins, cholesterol trafficking, and lipid metabolism. We will employ a combination of techniques established in the lab to test the hypothesis that ORP6 regulates cholesterol homeostasis in the CNS. Because lipoproteins that shuttle lipid to supply tissues of the body cannot cross the blood-brain barrier, the brain constitutes a particularly interesting microenvironment to study lipid homeostasis as it must be more tightly controlled. With functional biological tools in-hand to study ORP6, we are poised to dissect the fundamental mechanisms of action of this unique ORP family member in cellular cholesterol homeostasis and shed light on fundamental mechanisms of lipid transport in the CNS and mammalian cells.
动态平衡,也就是生命系统维持稳定的内部环境,是生命的核心原则。胆固醇动态平衡是一个保守的、必不可少的真核生物过程。在哺乳动物细胞内,细胞内膜胆固醇水平受到严格调控,具有复杂的细胞机制,以在不同的细胞内位置保持适当的胆固醇浓度。为此,囊泡性和非囊泡性胆固醇运输途径都是胆固醇在细胞间运输所必需的。尽管对这些途径进行了广泛的研究,但关于不同细胞间胆固醇转移的机制以及这些过程是如何调控的,仍然存在许多问题。氧合固醇结合相关蛋白(OSBP-Related Proteins,ORPs)是一类脂转移蛋白家族,参与多种细胞过程,与氧合固醇、细胞器间的接触、脂质代谢和非囊泡性固醇转运有关。我的NSERC研究项目的目标是调查LTPS在维持细胞和全身胆固醇动态平衡中的作用。氧固醇结合蛋白相关蛋白6(ORP6)是ORP家族中一个特性较差的成员,最近被认为是一种新的细胞内胆固醇水平调节因子。我们之前已经证明,ORP6调节胆固醇在细胞室(内小体和内质网)和质膜之间的运输以进行外流。然而,ORP6是如何调控这些通路的,以及它在大脑中表达最高的地方的功能尚不清楚。基因和蛋白质表达数据证明,相对于其他组织,ORP6在大脑中的表达丰富,更具体地说,相对于中枢神经系统(CNS)的其他细胞,在星形胶质细胞和神经元中的表达更丰富。为了研究ORP6如何调节胆固醇转运并确定其在全身胆固醇稳态中的生理作用,我们建议:1.研究ORP6在神经元和神经胶质胆固醇稳态中的作用。确定ORP6介导的胆固醇转运的机制。确定ORP6在胆固醇动态平衡中的生理作用。目前的提案结合了我在氧固醇结合蛋白、胆固醇运输和脂类代谢方面的独特专业知识。我们将使用实验室中建立的技术组合来测试ORP6调节中枢神经系统中胆固醇稳态的假设。因为运送脂质到身体组织供应的脂蛋白不能越过血脑屏障,大脑构成了研究脂质动态平衡的一个特别有趣的微环境,因为它必须受到更严格的控制。有了研究ORP6的功能生物学工具,我们准备剖析这个独特的ORP家族成员在细胞胆固醇稳态中的基本作用机制,并阐明中枢神经系统和哺乳动物细胞中脂质运输的基本机制。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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Ouimet, Mireille其他文献

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages.
  • DOI:
    10.1021/bc500517k
  • 发表时间:
    2015-03-18
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Sanchez-Gaytan, Brenda L.;Fay, Francois;Lobatto, Mark E.;Tang, Jun;Ouimet, Mireille;Kim, YongTae;van der Staay, Susanne E. M.;van Rijs, Sarian M.;Priem, Bram;Zhang, Liangfang;Fisher, Edward A.;Moore, Kathryn J.;Langer, Robert;Fayad, Zahi A.;Mulder, Willem J. M.
  • 通讯作者:
    Mulder, Willem J. M.
Autophagy Is Differentially Regulated in Leukocyte and Nonleukocyte Foam Cells During Atherosclerosis
  • DOI:
    10.1161/circresaha.121.320047
  • 发表时间:
    2022-03-18
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Robichaud, Sabrina;Rasheed, Adil;Ouimet, Mireille
  • 通讯作者:
    Ouimet, Mireille
miR-223 Exerts Translational Control of Proatherogenic Genes in Macrophages.
  • DOI:
    10.1161/circresaha.121.319120
  • 发表时间:
    2022-06-24
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    My-Anh Nguyen;Huy-Dung Hoang;Rasheed, Adil;Duchez, Anne-Claire;Wyatt, Hailey;Cottee, Mary Lynn;Graber, Tyson E.;Susser, Leah;Robichaud, Sabrina;Berber, Ibrahim;Geoffrion, Michele;Ouimet, Mireille;Kazan, Hilal;Maegdefessel, Lars;Mulvihill, Erin E.;Alain, Tommy;Rayner, Katey J.
  • 通讯作者:
    Rayner, Katey J.
Plasminogen Activator Inhibitor-1-Positive Platelet-Derived Extracellular Vesicles Predicts MACE and the Proinflammatory SMC Phenotype.
  • DOI:
    10.1016/j.jacbts.2022.05.002
  • 发表时间:
    2022-10
  • 期刊:
  • 影响因子:
    9.7
  • 作者:
    Jung, Richard G.;Duchez, Anne-Claire;Simard, Trevor;Dhaliwal, Shan;Gillmore, Taylor;Di Santo, Pietro;Labinaz, Alisha;Ramirez, F. Daniel;Rasheed, Adil;Robichaud, Sabrina;Ouimet, Mireille;Short, Spencer;Clifford, Cole;Xiao, Fengxia;Lordkipanidze, Marie;Burger, Dylan;Gadde, Suresh;Rayner, Katey J.;Hibbert, Benjamin
  • 通讯作者:
    Hibbert, Benjamin
Epoxycholesterol impairs cholesteryl ester hydrolysis in macrophage foam cells, resulting in decreased cholesterol efflux

Ouimet, Mireille的其他文献

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{{ truncateString('Ouimet, Mireille', 18)}}的其他基金

ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    RGPIN-2020-04851
  • 财政年份:
    2021
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual
ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    RGPIN-2020-04851
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual
ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    DGECR-2020-00017
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Launch Supplement

相似海外基金

ORP6による非小胞性脂質輸送の分子機構および生体機能の解明
ORP6非囊泡脂质转运的分子机制和生物学功能的阐明
  • 批准号:
    22K15360
  • 财政年份:
    2022
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    RGPIN-2020-04851
  • 财政年份:
    2021
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual
ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    RGPIN-2020-04851
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Grants Program - Individual
ROLE OF ORP6 IN INTRACELLULAR CHOLESTEROL TRAFFICKING
ORP6 在细胞内胆固醇贩运中的作用
  • 批准号:
    DGECR-2020-00017
  • 财政年份:
    2020
  • 资助金额:
    $ 2.7万
  • 项目类别:
    Discovery Launch Supplement
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