Role of extracellular vesicles in the regulation of immunometabolism in obesity

细胞外囊泡在肥胖免疫代谢调节中的作用

基本信息

  • 批准号:
    10439659
  • 负责人:
  • 金额:
    $ 58.83万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary The worldwide prevalence of obesity has reached pandemic proportions. Obesity has strong inflammatory underpinnings, which are associated with the development of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). However, the mechanisms by which obesity provokes aberrant inflammation are not clearly defined. In this study, we aim to demonstrate that in obesity, the mTOR pathway enhances the biogenesis and secretion of pro-inflammatory extracellular vesicles (EVs) carrying a distinct set of extracellular RNAs (exRNAs) from hepatocytes and that these hepatocyte-derived EVs (H-EVs) cause the aberrant inflammation. EVs, including exosomes (30–150 nm) and microvesicles (100–1000 nm), are released from many cell types into the extracellular space and are distributed in body fluids. These EVs are taken up by neighboring or distant cells and subsequently modulate functions of recipient cells. Using novel computational methods9, we identified strong associations between human genetic variations of genes regulating EV biogenesis and metabolic syndrome, particularly T2D. Our analyses of EVs from adolescent obese patients undergoing bariatric surgery have shown that serum EV concentration is inversely correlated to metabolic improvements in insulin sensitivity and inflammation post-surgery, with unique EVs’ exRNA profiles. Further, our newly established mouse model that permits monitoring of specific cell type-derived EVs in vivo indicates that in obesity, H-EVs behave like a pathogen recognized by macrophages and induce inflammation. Mechanistically, we found that in hepatocytes, the insulin-mTOR pathway enhances secretion of EVs and that insulin- stimulated EVs are more pro-inflammatory in activating macrophages. We have also discovered that a component of the RNA silencing machinery is a mediator of the pro-inflammatory EVs and is required for the EV-induced macrophage activation. These preliminary data suggest unique and pivotal roles for H-EVs, leading us to hypothesize that during the development of hyperinsulinemia, hepatocytes secrete pathologic EVs carrying unique exRNAs which are sensed by recipient macrophages, promoting aberrant inflammation. Studies in this proposal will: (1) define the molecular pathway that confers the proinflammatory trait to the H- EVs, (2) determine the role of RNA silencing machinery in macrophages as a mediator of pro-inflammatory EVs, and (3) evaluate the role of EVs in immunometabolism in human obese patients. By utilizing our novel mouse models coupled with access to human samples, our systematical approaches will demonstrate novel mechanisms concerning how the pathogenicity of H-EVs is involved in the development of inflammation in hyperinsulinemia and obesity.
项目摘要 肥胖症在世界范围内的流行已达到大流行的程度。肥胖具有强烈的炎症性 基础,这与2型糖尿病(T2 D)和非酒精性糖尿病的发展有关。 脂肪性肝炎(NASH)。然而,肥胖引起异常炎症的机制并不 明确了在这项研究中,我们的目的是证明在肥胖症中,mTOR通路增强了肥胖症的发病率。 促炎细胞外囊泡(EV)的生物发生和分泌, 这些细胞外RNA(exRNA)来自肝细胞,并且这些肝细胞衍生的EV(H-EV)引起肝细胞的细胞外RNA(exRNA)。 异常炎症 EV,包括外来体(30-150 nm)和微泡(100-1000 nm),从许多细胞类型释放 进入细胞外间隙并分布在体液中。这些电动汽车被邻近的或 远距离细胞,随后调节受体细胞的功能。使用新的计算方法9,我们 确定了调节EV生物发生的基因的人类遗传变异之间的强关联, 代谢综合征,尤其是T2 D。我们分析了青少年肥胖患者接受 减肥手术显示,血清EV浓度与代谢改善呈负相关 在胰岛素敏感性和术后炎症中的作用,具有独特的EV的exRNA谱。此外,我们的新 建立的小鼠模型允许在体内监测特定细胞类型来源的EV,这表明, 在肥胖症中,H-EV表现得像被巨噬细胞识别的病原体并诱导炎症。机械地说, 我们发现,在肝细胞中,胰岛素-mTOR通路增强EV的分泌, 受刺激EV在激活巨噬细胞方面更促炎。我们还发现, RNA沉默机制的组分是促炎性EV的介体,并且是促炎性EV所需的。 EV诱导的巨噬细胞活化。这些初步数据表明H-EV的独特和关键作用, 这使我们假设在高胰岛素血症的发展过程中,肝细胞分泌 携带由受体巨噬细胞感知的独特exRNA的病理性EV, 异常炎症 本研究将:(1)确定将促炎特性赋予H- EVs,(2)确定巨噬细胞中RNA沉默机制作为促炎介质的作用, EV,和(3)评估EV在人类肥胖患者的免疫代谢中的作用。 通过利用我们新型的小鼠模型以及人类样本,我们的系统方法 将展示关于H-EV的致病性如何参与H-EV感染的新机制。 高胰岛素血症和肥胖症中炎症的发展。

项目成果

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Takahisa Nakamura其他文献

Takahisa Nakamura的其他文献

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{{ truncateString('Takahisa Nakamura', 18)}}的其他基金

Establish a novel mouse model tracking multiple extracellular vesicles
建立追踪多个细胞外囊泡的新型小鼠模型
  • 批准号:
    10452618
  • 财政年份:
    2021
  • 资助金额:
    $ 58.83万
  • 项目类别:
Establish a novel mouse model tracking multiple extracellular vesicles
建立追踪多个细胞外囊泡的新型小鼠模型
  • 批准号:
    10288370
  • 财政年份:
    2021
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of extracellular vesicles in the regulation of immunometabolism in obesity
细胞外囊泡在肥胖免疫代谢调节中的作用
  • 批准号:
    10641864
  • 财政年份:
    2020
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of extracellular vesicles in the regulation of immunometabolism in obesity
细胞外囊泡在肥胖免疫代谢调节中的作用
  • 批准号:
    10289446
  • 财政年份:
    2020
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of extracellular vesicles in the regulation of immunometabolism in obesity
细胞外囊泡在肥胖免疫代谢调节中的作用
  • 批准号:
    10053924
  • 财政年份:
    2020
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of extracellular vesicles in the regulation of immunometabolism in obesity
细胞外囊泡在肥胖免疫代谢调节中的作用
  • 批准号:
    10206132
  • 财政年份:
    2020
  • 资助金额:
    $ 58.83万
  • 项目类别:
Detection and characterization of cell type-specific extracellular vesicles in obesity-driven hepatocellular carcinoma
肥胖导致的肝细胞癌中细胞类型特异性细胞外囊泡的检测和表征
  • 批准号:
    9806072
  • 财政年份:
    2019
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of Hepatic RNA Silencing in Insulin Resistance and Obesity
肝脏 RNA 沉默在胰岛素抵抗和肥胖中的作用
  • 批准号:
    9331616
  • 财政年份:
    2016
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of Hepatic RNA Silencing in Insulin Resistance and Obesity
肝脏 RNA 沉默在胰岛素抵抗和肥胖中的作用
  • 批准号:
    9974294
  • 财政年份:
    2016
  • 资助金额:
    $ 58.83万
  • 项目类别:
Role of Hepatic RNA Silencing in Insulin Resistance and Obesity
肝脏 RNA 沉默在胰岛素抵抗和肥胖中的作用
  • 批准号:
    9173255
  • 财政年份:
    2016
  • 资助金额:
    $ 58.83万
  • 项目类别:

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向路易斯安那州学校传播青少年肥胖预防干预措施
  • 批准号:
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Exploring the Familial Reach of Adolescent Obesity Treatment
探索青少年肥胖治疗的家庭影响力
  • 批准号:
    10589875
  • 财政年份:
    2022
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Interpersonal- and Community-Level Risk Factors for Adolescent Obesity: An Examination of Sexual Identity, School Violence, and School Climate in a Large Sample of Urban Adolescents
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    10064659
  • 财政年份:
    2020
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    $ 58.83万
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Interpersonal- and Community-Level Risk Factors for Adolescent Obesity: An Examination of Sexual Identity, School Violence, and School Climate in a Large Sample of Urban Adolescents
青少年肥胖的人际和社区层面的风险因素:对大样本城市青少年的性别认同、学校暴力和学校氛围的调查
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父母在青少年肥胖治疗中的作用:青少年随机对照试验
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  • 财政年份:
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