Impact of the Adipose Tissue Microenvironment on Atherosclerosis

脂肪组织微环境对动脉粥样硬化的影响

基本信息

  • 批准号:
    10063545
  • 负责人:
  • 金额:
    $ 51.09万
  • 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:
    2017-12-15 至 2022-11-30
  • 项目状态:
    已结题

项目摘要

ABSTRACT Changes in the abundance and phenotypes of adipose tissue immune cells are a major determinant of systemic inflammation and insulin resistance during excess weight gain. Adipocyte expression of the class II major histocompatibility complex (MHCII) occurs early during high-fat diet (HFD) challenge and parallels pro- inflammatory changes in MHCII-activated CD4+ adipose resident T cells (ARTs) implicating the adipocyte as an instigator of obesity-induced inflammation. Adipocyte-specific MHCII null (aMHCII-/-) mice created to test this hypothesis 1) developed substantially less visceral adipose tissue (VAT) inflammation than their wild-type (WT) littermates when challenged with HFD, despite identical changes in body weight and %body fat, 2) had markedly more VAT regulatory T cells (Tregs), but not in other peripheral sites; 3) were more insulin sensitive with better glucose homeostasis and 4) when bred into an atherosclerosis prone LDLR-/- background, attenuated accelerated atherosclerosis without affecting plasma cholesterol and triglyceride levels. Tregs are a major component of the CD4+ ART population in lean mice, where they suppress inflammation to maintain normal VAT metabolism, but dramatically decrease during HFD-challenge. However, VAT Tregs are preserved in HFD-fed aMHCII-/- mice, which likely explains the improved metabolic and cardiovascular phenotype in these mice. The aMHCII-/- mutation, thus, provides a unique opportunity to specifically alter adipose inflammation, independent of obesity, dyslipidemia, and changes in peripheral T cells to investigate its impact on obesity- induced complications, particularly atherosclerosis. We hypothesize that decreased adipose inflammation attenuates atherosclerosis even in the presence of obesity. Specific Aims will address: 1) the effect of A) aMHCII-deficiency and B) visceral adipose tissue (VAT)-specific Treg depletion (via cells with defective VAT Treg homeostasis or an IL-33 receptor blocking antibody which inhibits IL-33-induced VAT Treg proliferation) on diet-induced atherosclerosis; 2) whether A) constitutive, adipocyte-specific MHCII overexpression promotes adipose inflammation to enhance atherosclerosis, and B) administration of IL-33 attenuates atherosclerosis through a VAT Treg-dependent mechanism; and 3) changes in the immune cell composition and molecular phenotypes in aortic lesions in mice with and without aMHCII mutations using T cell flow analyses of aorta, laser capture microdissection of plaque macrophages, and investigation of macrophage trafficking from VAT to aorta. The results of this investigation using adipocyte MHCII knock-in/knock-out models and several novel approaches to specifically alter VAT, but not peripheral, Tregs will determine the contributions of adipose tissue inflammation and VAT Tregs to the pathogenesis of obesity-associated atherosclerosis. This mechanistic insight sets the stage for development of better immune-based therapeutic strategies to combat CVD in the setting of obesity.
摘要 脂肪组织免疫细胞的丰度和表型的变化是一个主要的决定因素, 全身炎症和胰岛素抵抗。II类脂肪细胞表达 主要组织相容性复合体(MHCII)在高脂饮食(HFD)挑战期间早期出现,并与前 MHCII激活的CD 4+脂肪驻留T细胞(ARTs)的炎症变化暗示脂肪细胞是 肥胖引发炎症的罪魁祸首创建脂肪细胞特异性MHCII空(aMHCII-/-)小鼠以测试 这一假设1)与野生型相比, (WT)当用HFD激发时,尽管体重和%体脂的变化相同,但2) 显著增加VAT调节性T细胞(Tcells),但在其他外周部位没有; 3)胰岛素敏感性更高 具有更好的葡萄糖稳态和4)当繁殖到动脉粥样硬化倾向的LDLR-/-背景中时, 减弱加速的动脉粥样硬化而不影响血浆胆固醇和甘油三酯水平。Tumblr是一个 瘦小鼠中CD 4 + ART群体的主要组成部分,在那里它们抑制炎症, 正常的VAT代谢,但在HFD激发期间显著降低。然而,增值税税率被保留 在HFD喂养的aMHCII-/-小鼠中,这可能解释了这些小鼠中代谢和心血管表型的改善。 小鼠因此,aMHCII-/-突变提供了特异性改变脂肪炎症的独特机会, 独立于肥胖、血脂异常和外周T细胞的变化,以研究其对肥胖的影响- 引起并发症,特别是动脉粥样硬化。我们假设减少脂肪炎症 即使在肥胖症的情况下也能减弱动脉粥样硬化。具体目标将解决:1)A)的影响 aMHCII缺乏和B)内脏脂肪组织(VAT)特异性Treg耗竭(通过具有缺陷性VAT的细胞 Treg稳态或抑制IL-33诱导的VAT Treg增殖的IL-33受体阻断抗体) 2)A)组成性脂肪细胞特异性MHCII过表达是否促进 脂肪炎症以增强动脉粥样硬化,和B)施用IL-33减弱动脉粥样硬化 通过VAT Treg依赖性机制;和3)免疫细胞组成和分子水平的变化, 使用主动脉的T细胞流动分析在具有和不具有aMHCII突变的小鼠中的主动脉病变中的表型, 斑块巨噬细胞的激光捕获显微切割,以及巨噬细胞从VAT到 主动脉本研究使用脂肪细胞MHCII敲入/敲除模型和几种新的MHCII基因敲除模型, 特别是改变VAT的方法,但不是外围的,TdR将决定脂肪的贡献, 组织炎症和血管内皮生长因子对肥胖相关动脉粥样硬化发病机制的影响。这 机械的洞察力为开发更好的基于免疫的治疗策略奠定了基础, 心血管疾病在肥胖的背景下。

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Association of Serum Aldosterone and Plasma Renin Activity With Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.
  • DOI:
    10.1161/circulationaha.120.050896
  • 发表时间:
    2021-06-15
  • 期刊:
  • 影响因子:
    37.8
  • 作者:
    Joseph JJ;Pohlman NK;Zhao S;Kline D;Brock G;Echouffo-Tcheugui JB;Sims M;Effoe VS;Wu WC;Kalyani RR;Wand GS;Kluwe B;Hsueh WA;Abdalla M;Shimbo D;Golden SH
  • 通讯作者:
    Golden SH
Adipocytes, Innate Immunity and Obesity: A Mini-Review.
脂肪细胞、先天免疫和肥胖:小型回顾。
  • DOI:
    10.3389/fimmu.2021.650768
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Blaszczak AM;Jalilvand A;Hsueh WA
  • 通讯作者:
    Hsueh WA
Adipocyte DIO2 Expression Increases in Human Obesity but Is Not Related to Systemic Insulin Sensitivity.
  • DOI:
    10.1155/2018/2464652
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Bradley D;Liu J;Blaszczak A;Wright V;Jalilvand A;Needleman B;Noria S;Renton D;Hsueh W
  • 通讯作者:
    Hsueh W
Obesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance.
  • DOI:
    10.20900/immunometab20200023
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Blaszczak, Alecia M;Bernier, Matt;Hsueh, Willa A
  • 通讯作者:
    Hsueh, Willa A
Association of Adiposity With Incident Diabetes Among Black Adults in the Jackson Heart Study.
  • DOI:
    10.1161/jaha.120.020716
  • 发表时间:
    2021-09-21
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Joseph JJ;Kluwe B;Echouffo-Tcheugui JB;Zhao S;Brock G;Kline D;Odei JB;Kalyani RR;Bradley DP;Hsueh WA;Sims M;Golden SH
  • 通讯作者:
    Golden SH
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Willa A Hsueh其他文献

Pharmacologic treatment options for prediabetes
针对糖尿病前期的药物治疗选择
  • DOI:
    10.1038/ncpendmet0842
  • 发表时间:
    2008-06-03
  • 期刊:
  • 影响因子:
    40.000
  • 作者:
    Willa A Hsueh;Yehuda Handelsman
  • 通讯作者:
    Yehuda Handelsman
816-4 Effect of glucose lowering on coronary circulatory dysfunction in type 2 diabetes mellitus
  • DOI:
    10.1016/s0735-1097(04)91437-4
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Alvaro D Facta;John O Prior;Thomas H Schindler;Jerson Cadenas;Manuel J Quinones;Willa A Hsueh;Heinrich R Schelbert
  • 通讯作者:
    Heinrich R Schelbert

Willa A Hsueh的其他文献

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{{ truncateString('Willa A Hsueh', 18)}}的其他基金

Postdoctoral Training in Cardiometabolic Science
心脏代谢科学博士后培训
  • 批准号:
    10684162
  • 财政年份:
    2020
  • 资助金额:
    $ 51.09万
  • 项目类别:
Postdoctoral Training in Cardiometabolic Science
心脏代谢科学博士后培训
  • 批准号:
    10242188
  • 财政年份:
    2020
  • 资助金额:
    $ 51.09万
  • 项目类别:
Postdoctoral Training in Cardiometabolic Science
心脏代谢科学博士后培训
  • 批准号:
    10473596
  • 财政年份:
    2020
  • 资助金额:
    $ 51.09万
  • 项目类别:
Postdoctoral Training in Cardiometabolic Science
心脏代谢科学博士后培训
  • 批准号:
    10024795
  • 财政年份:
    2020
  • 资助金额:
    $ 51.09万
  • 项目类别:
Chemical Biology of Nuclear Receptor Action in the Macrophage
巨噬细胞核受体作用的化学生物学
  • 批准号:
    7868719
  • 财政年份:
    2010
  • 资助金额:
    $ 51.09万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    7425746
  • 财政年份:
    2008
  • 资助金额:
    $ 51.09万
  • 项目类别:
Transcriptional Genomics Core
转录基因组学核心
  • 批准号:
    7500497
  • 财政年份:
    2007
  • 资助金额:
    $ 51.09万
  • 项目类别:
Human Genetics Core
人类遗传学核心
  • 批准号:
    7500502
  • 财政年份:
    2007
  • 资助金额:
    $ 51.09万
  • 项目类别:
Mouse Phenotyping Core
小鼠表型核心
  • 批准号:
    7500488
  • 财政年份:
    2007
  • 资助金额:
    $ 51.09万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7500510
  • 财政年份:
    2007
  • 资助金额:
    $ 51.09万
  • 项目类别:

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Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
    321208980
  • 财政年份:
    2016
  • 资助金额:
    $ 51.09万
  • 项目类别:
    Research Grants
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8827438
  • 财政年份:
    2014
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    $ 51.09万
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Induction of brown-like adipocytes in white adipose tissue by food-derived factors
食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 51.09万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
    2014
  • 资助金额:
    $ 51.09万
  • 项目类别:
    Research Fellowships
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8828181
  • 财政年份:
    2013
  • 资助金额:
    $ 51.09万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8520690
  • 财政年份:
    2013
  • 资助金额:
    $ 51.09万
  • 项目类别:
Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
    2013
  • 资助金额:
    $ 51.09万
  • 项目类别:
Effect of exercise training on formation of brite adipocytes within white adipose tissue
运动训练对白色脂肪组织内脂肪细胞形成的影响
  • 批准号:
    23700778
  • 财政年份:
    2011
  • 资助金额:
    $ 51.09万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
    $ 51.09万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
  • 批准号:
    7610781
  • 财政年份:
    2007
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