Targeting the Enterocyte to Prevent Vascular Inflammation

靶向肠上皮细胞预防血管炎症

基本信息

  • 批准号:
    10406270
  • 负责人:
  • 金额:
    $ 57.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-06-01 至 2023-05-31
  • 项目状态:
    已结题

项目摘要

Abstract Feeding low density lipoprotein receptor null (Ldlr-/-) mice a Western Diet (WD) not only causes dyslipidemia and atherosclerosis, it also causes vascular inflammation of brain, kidneys, and the small intestine mesentery. The intestine contains more immune cells than any other organ in the body. The number and activation state of these immune cells is in part governed by bacterial and viral products that get past the enterocytes, but they are also governed by lipid signaling molecules such as lysophosphatidic acid 18:1 (LPA 18:1). A major precursor to LPA 18:1 is lysophosphatidylcholine 18:1 (LysoPC 18:1). LysoPC 18:1 is formed in enterocytes preferentially using oleic acid synthesized in the enterocytes by Stearoyl Co-A desaturase-1 (Scd1). Enterocyte LysoPC 18:1 is converted to LPA 18:1 by the action of enterocyte lysophospholipase D (autotaxin). Dietary fat alters the microbiome and increases intestinal permeability via signaling pathways dually controlled by the levels of bacterial lipopolysaccharide (LPS), and enterocyte generated lipid signaling molecules such as LPA 18:1. We hypothesize that the levels of LPS and molecules such as LPA 18:1 in the small intestine determine the systemic response to dietary fat challenge. Aim 1 will determine the role and mechanism(s) of enterocyte Scd1 in diet-induced dyslipidemia and vascular inflammation. Administering LPA 18:1 or LysoPC 18:1 to Ldlr-/- mice on a chow diet mimicked feeding these mice WD. We generated Ldlr-/- mice with enterocyte knockdown of Scd1, which on WD lowered enterocyte levels of LysoPC 18:1 and LPA 18:1. We will determine if enterocyte knockdown of Scd1 favorably alters: 1) aortic atherosclerosis; 2) cholesterol and lipid absorption; 3) composition of the microbiome; 4) microbiome-host interactions; 5) intestinal permeability and serum endotoxin levels; 6) lipids secreted from enterocytes (determined using a lipidomics approach); and 7) Notch pathway to ameliorate diet-induced vascular inflammation. Aim 2 will determine the role and mechanism(s) of enterocyte lysophospholipase D (autotaxin). We generated Ldlr-/- mice with enterocyte knockdown of Enpp2, the gene for autotaxin. Enterocyte knockdown of Enpp2 reduced levels of LPA 18:1 in enterocytes and plasma, and decreased WD-induced dyslipidemia and systemic inflammation. We will determine if enterocyte knockdown of Enpp2 reduces aortic atherosclerosis. We hypothesize that increased levels of enterocyte unsaturated LPA species such as LPA 18:1 lead to the oxidation of chylomicrons secreted from enterocytes, which leads to vascular inflammation. We will determine if enterocyte knockdown of Enpp2 favorably alters these events. Aim 3 will determine the mechanism(s) of action of a concentrate of tomatoes expressing the apoA-I mimetic peptide 6F from a transgene (Tg6F) in ameliorating diet-induced dyslipidemia and vascular inflammation. We will determine if Tg6F mimics enterocyte knockdown of Scd1 and Enpp2. We will determine the lipids removed from mouse jejunum by Tg6F. We will determine if Tg6F preserves the Notch pathway and prevents vascular inflammation in mice fed chow supplemented with LysoPC 18:1, or LPA 18:1 or fed WD.
摘要 用西方饮食(WD)喂养低密度脂蛋白受体缺失(Ldlr-/-)小鼠不仅会导致血脂异常, 和动脉粥样硬化,它还引起脑、肾和小肠肠系膜的血管炎症。 肠道含有比身体任何其他器官更多的免疫细胞。的数量和激活状态 这些免疫细胞在一定程度上是由细菌和病毒的产物控制的,这些产物可以通过肠上皮细胞, 也由脂质信号分子如溶血磷脂酸18:1(LPA 18:1)控制。一个主要 LPA 18:1的前体是溶血磷脂酰胆碱18:1(LysoPC 18:1)。LysoPC 18:1在肠上皮细胞中形成 优先使用在肠细胞中由硬脂酰辅酶A去饱和酶-1(Scd 1)合成的油酸。肠细胞 LysoPC 18:1通过肠细胞溶血磷脂酶D(自分泌运动因子)的作用转化为LPA 18:1。膳食脂肪 改变微生物组,并通过双重控制的信号通路增加肠道通透性。 细菌脂多糖(LPS)和肠细胞产生的脂质信号分子(如LPA)水平 十八比一我们推测,小肠中LPS和LPA 18:1等分子的水平决定了 对膳食脂肪挑战的全身反应。目的1明确肠上皮细胞的作用和机制 膳食诱导的血脂异常和血管炎症中的scd 1。将LPA 18:1或LysoPC 18:1给予Ldlr-/- 喂食饲料的小鼠模仿喂食WD。我们用肠上皮细胞敲低产生了Ldlr-/-小鼠, 的Scd 1,这对WD降低肠细胞水平的LysoPC 18:1和LPA 18:1。我们将确定肠上皮细胞 Scd 1的敲除有利地改变:1)主动脉粥样硬化; 2)胆固醇和脂质吸收; 3) 微生物组的组成; 4)微生物组-宿主相互作用; 5)肠通透性和血清内毒素 水平; 6)从肠上皮细胞分泌的脂质(使用脂质组学方法测定);和7)Notch途径, 改善饮食引起的血管炎症。目的2将确定肠细胞的作用和机制 溶血磷脂酶D(自分泌运动因子)。我们产生了Ldlr-/-小鼠,其肠上皮细胞敲低了Enpp 2, 自分泌运动因子Enpp 2的肠细胞敲低降低了肠细胞和血浆中LPA 18:1的水平, 降低WD诱导的血脂异常和全身炎症。我们将确定肠上皮细胞敲除 Enpp 2减少主动脉粥样硬化。我们假设肠上皮细胞不饱和LPA水平的增加 例如LPA 18:1的种类导致肠细胞分泌的乳糜微粒氧化,这导致 血管炎症我们将确定是否肠上皮细胞敲低Enpp 2有利地改变这些事件。目的 3将确定表达apoA-I模拟物的番茄浓缩物的作用机制 来自转基因的肽6 F(Tg 6 F)在改善饮食诱导的血脂异常和血管炎症中的作用。我们 将确定Tg 6 F是否模拟Scd 1和Enpp 2的肠细胞敲低。我们将确定去除的脂质 小鼠空肠Tg 6 F。我们将确定Tg 6 F是否保留了Notch通路,并阻止血管生成。 在喂食补充有LysoPC 18:1或LPA 18:1的食物或喂食WD的小鼠中,

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The role of gut-derived oxidized lipids and bacterial lipopolysaccharide in systemic inflammation and atherosclerosis.
  • DOI:
    10.1097/mol.0000000000000841
  • 发表时间:
    2022-10-01
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Wang, Huan;Reddy, Srinivasa T.;Fogelman, Alan M.
  • 通讯作者:
    Fogelman, Alan M.
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Alan M Fogelman其他文献

Mechanisms of Disease: proatherogenic HDL—an evolving field
疾病机制:促动脉粥样硬化性高密度脂蛋白——一个不断发展的领域
  • DOI:
    10.1038/ncpendmet0245
  • 发表时间:
    2006-09-01
  • 期刊:
  • 影响因子:
    40.000
  • 作者:
    Mohamad Navab;Gattadahalli M Anantharamaiah;Srinivasa T Reddy;Brian J Van Lenten;Benjamin J Ansell;Alan M Fogelman
  • 通讯作者:
    Alan M Fogelman
Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention
载脂蛋白 A-I 模拟肽及其在动脉粥样硬化预防中的作用
  • DOI:
    10.1038/ncpcardio0661
  • 发表时间:
    2006-10-01
  • 期刊:
  • 影响因子:
    44.200
  • 作者:
    Mohamad Navab;GM Anantharamaiah;Srinivasa T Reddy;Alan M Fogelman
  • 通讯作者:
    Alan M Fogelman
When good cholesterol goes bad
当好胆固醇变坏时
  • DOI:
    10.1038/nm0904-902
  • 发表时间:
    2004-09-01
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Alan M Fogelman
  • 通讯作者:
    Alan M Fogelman

Alan M Fogelman的其他文献

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{{ truncateString('Alan M Fogelman', 18)}}的其他基金

Targeting the Enterocyte to Prevent Vascular Inflammation
靶向肠上皮细胞预防血管炎症
  • 批准号:
    10175015
  • 财政年份:
    2019
  • 资助金额:
    $ 57.44万
  • 项目类别:
Targeting the Enterocyte to Prevent Vascular Inflammation
靶向肠上皮细胞预防血管炎症
  • 批准号:
    9797102
  • 财政年份:
    2019
  • 资助金额:
    $ 57.44万
  • 项目类别:
LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS (CORE A)
动脉粥样硬化中的脂质和脂蛋白代谢(核心 A)
  • 批准号:
    8167070
  • 财政年份:
    2009
  • 资助金额:
    $ 57.44万
  • 项目类别:
Accounting and Administrative Services Core
会计和行政服务核心
  • 批准号:
    7647670
  • 财政年份:
    2009
  • 资助金额:
    $ 57.44万
  • 项目类别:
An In-Vitro and In-Vivo Approach to Artery Wall Inflammation
动脉壁炎症的体外和体内方法
  • 批准号:
    7647662
  • 财政年份:
    2009
  • 资助金额:
    $ 57.44万
  • 项目类别:
LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS (CORE A)
动脉粥样硬化中的脂质和脂蛋白代谢(核心 A)
  • 批准号:
    7951528
  • 财政年份:
    2009
  • 资助金额:
    $ 57.44万
  • 项目类别:
LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS (CORE A)
动脉粥样硬化中的脂质和脂蛋白代谢(核心 A)
  • 批准号:
    7717969
  • 财政年份:
    2007
  • 资助金额:
    $ 57.44万
  • 项目类别:
LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS (CORE A)
动脉粥样硬化中的脂质和脂蛋白代谢(核心 A)
  • 批准号:
    7606765
  • 财政年份:
    2007
  • 资助金额:
    $ 57.44万
  • 项目类别:
LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS (CORE A)
动脉粥样硬化中的脂质和脂蛋白代谢(核心 A)
  • 批准号:
    7205426
  • 财政年份:
    2004
  • 资助金额:
    $ 57.44万
  • 项目类别:
In Vitro /In Vivo Approach to Artery Wall Inflammation
动脉壁炎症的体外/体内方法
  • 批准号:
    6758073
  • 财政年份:
    2003
  • 资助金额:
    $ 57.44万
  • 项目类别:

相似海外基金

New diagnostic and therapeutic strategies for atherosclerosis using newly developed apolipoprotein A-I mimetic peptide
使用新开发的载脂蛋白 A-I 模拟肽治疗动脉粥样硬化的新策略
  • 批准号:
    24591123
  • 财政年份:
    2012
  • 资助金额:
    $ 57.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Novel Apolipoprotein A-I Mimetic Peptides: a Research Tool and a Therapeutic Agent to Study and Treat Atherosclerosis
新型载脂蛋白 A-I 模拟肽:研究和治疗动脉粥样硬化的研究工具和治疗剂
  • 批准号:
    nhmrc : 1003106
  • 财政年份:
    2011
  • 资助金额:
    $ 57.44万
  • 项目类别:
    NHMRC Project Grants
Animal model of autoimmune-induced atherosclerosis : Clinical significance of autoantibody against apolipoprotein A-I
自身免疫性动脉粥样硬化动物模型:载脂蛋白A-I自身抗体的临床意义
  • 批准号:
    08557133
  • 财政年份:
    1996
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    $ 57.44万
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    Grant-in-Aid for Scientific Research (A)
ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION
动脉粥样硬化和载脂蛋白 A-I 调节
  • 批准号:
    3472495
  • 财政年份:
    1988
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    $ 57.44万
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ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION
动脉粥样硬化和载脂蛋白 A-I 调节
  • 批准号:
    3472494
  • 财政年份:
    1988
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    $ 57.44万
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ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION
动脉粥样硬化和载脂蛋白 A-I 调节
  • 批准号:
    3472492
  • 财政年份:
    1988
  • 资助金额:
    $ 57.44万
  • 项目类别:
ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION
动脉粥样硬化和载脂蛋白 A-I 调节
  • 批准号:
    2220202
  • 财政年份:
    1988
  • 资助金额:
    $ 57.44万
  • 项目类别:
ATHEROSCLEROSIS AND APOLIPOPROTEIN A-I REGULATION
动脉粥样硬化和载脂蛋白 A-I 调节
  • 批准号:
    3472493
  • 财政年份:
    1988
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    $ 57.44万
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  • 批准号:
    3348940
  • 财政年份:
    1985
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    $ 57.44万
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APOLIPOPROTEIN A-I GENE POLYMORPHISM AND ATHEROSCLEROSIS
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  • 批准号:
    3348942
  • 财政年份:
    1985
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    $ 57.44万
  • 项目类别:
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