Environmental obesogens reduce Thy1 expression and promote obesity

环境致肥胖因素降低Thy1表达并促进肥胖

基本信息

  • 批准号:
    8569119
  • 负责人:
  • 金额:
    $ 19.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-19 至 2015-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Obesity has risen dramatically over the last 30 years. In the U.S. alone, 60 million people are defined as clinically obese. Especially concerning is the nearly epidemic rate of childhood obesity. Obesity occurs through excessive adipogenesis (formation of adipocytes) or through increases in established adipocyte size. Environmental toxicants termed obesogens disrupt the endocrine system and can increase adipogenesis. Tributyltin (TBT), dichlorodiphenyl-dichloroethylene (DDE), bisphenol-A diglycidyl ether (BADGE), and tetrabromobisphenol-A (TBBPA), have been reported to increase obesity. The mechanism(s) by which xenobiotic obesogens function to disrupt the endocrine system and increase rates of obesity requires active investigation. Our work focuses on the surface glycoprotein, Thy1 (CD90). Thy1 is an glycophosphatidylinositol (GPI)-anchored membrane protein expressed on subsets of neurons, stem cells and other cell types. We discovered that fibroblasts are heterogeneous for expression of Thy1 and that only Thy1+ fibroblasts can differentiate into scar-forming myofibroblasts and only Thy1-/low fibroblasts can differentiate int adipocytes. In this R21 application, we hypothesize that there is a direct role for Thy1 in preventing adipogenesis. Our supporting data show that depletion of Thy1 increases adipogenesis while over- expression of Thy1 impairs adipogenesis. These data support the concept that Thy1 is more than a marker and that Thy1 can function to modify cell fate. We also discovered that Thy1 expression is reduced in both human and mouse multipotent stromal cells (MSCs) after exposure to TBBPA, BADGE and TBT. Importantly, one mechanism by which obesogens may function is to reprogram the epigenetic code of MSCs to alter physiology. The Thy1 locus contains multiple CpG islands that can be controlled epigenetically and may be key targets of obesogens. Developmental exposure to obesogens may reprogram Thy1 expression levels and modify physiology long after exposure. Therefore, we hypothesize that environmental obesogens alter Thy1 expression to increase adipogenesis and obesity. To investigate this hypothesis we have developed the following aims. Aim 1: Test the hypothesis that environmental obesogens diminish Thy1 expression and activity in multipotent stromal cells to increase adipogenesis. Aim 2: Test the hypothesis that developmental exposure to obesogens reduces Thy1 expression and increases adipogenesis and obesity in vivo. The results of these studies will show for the first time that Thy1 expression is reduced by environmental obesogens and this reduction is key to the mechanism whereby obesogens increase adipogenesis and obesity.
描述(由申请人提供):在过去的30年里,肥胖症急剧上升。仅在美国,就有6000万人被定义为临床肥胖症。尤其令人担忧的是儿童肥胖症的近乎流行的比率。肥胖是通过过度的脂肪生成(脂肪细胞的形成)或通过已建立的脂肪细胞大小的增加而发生的。被称为肥胖的环境毒物会扰乱内分泌系统,并会增加脂肪的生成。据报道,三丁基锡(TBT)、二氯二苯二氯乙烯(DDE)、双酚-A二缩水甘油醚(BAGE)和四溴双酚-A(TBBPA)会增加肥胖。外来致肥者扰乱内分泌系统并增加肥胖率的机制(S)需要积极研究。我们的工作重点是表面糖蛋白Thy1(CD90)。Thy1是一种糖磷脂酰肌醇(GPI)锚定的膜蛋白,表达于神经元、干细胞和其他类型的细胞亚群。我们发现成纤维细胞中Thy1的表达是异质性的,只有Thy1+成纤维细胞才能分化为瘢痕形成肌成纤维细胞,只有Thy1-/Low成纤维细胞才能分化为间脂肪细胞。在R21的应用中,我们假设Thy1在防止脂肪生成方面有直接作用。我们的支持数据表明,Thy1的缺失增加了脂肪的生成,而Thy1的过度表达则削弱了脂肪的生成。这些数据支持这样的概念,即Thy1不仅仅是一个标记,而且Thy1可以改变细胞的命运。我们还发现,在人和小鼠多能基质细胞(MSCs)中,暴露于TBBPA、BAGE和TBT后,Thy1的表达都降低了。重要的是,致肥者可能发挥作用的一个机制是重新编程MSCs的表观遗传密码以改变生理。Thy1基因座包含多个CpG岛,这些岛可以通过表观遗传进行控制,可能是致肥者的关键靶点。发育期暴露于肥胖源可能会改变Thy1的表达水平,并在暴露后很长时间内改变生理功能。因此,我们假设环境致肥者改变了Thy1的表达,从而增加了脂肪生成和肥胖。为了研究这一假设,我们制定了以下目标。目的1:验证环境致病因子降低Thy1在多能基质细胞中的表达和活性以促进脂肪生成的假说。目的2:在体内验证发育过程中暴露于肥胖物质降低Thy1表达并增加脂肪生成和肥胖的假说。这些研究的结果将首次表明,环境致肥者减少了Thy1的表达,这种减少是致肥者增加脂肪生成和肥胖的关键机制。

项目成果

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RICHARD P. PHIPPS其他文献

RICHARD P. PHIPPS的其他文献

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{{ truncateString('RICHARD P. PHIPPS', 18)}}的其他基金

Thy1 expression, adpogenesis, inflammation and orbital remodeling mechanisms in Thyroid Eye Disease
甲状腺眼病中 Thy1 表达、脂肪生成、炎症和眼眶重塑机制
  • 批准号:
    9213038
  • 财政年份:
    2017
  • 资助金额:
    $ 19.19万
  • 项目类别:
Dysregulation of common metabolic and transcriptional pathways in heart and lung fibrosis
心肺纤维化常见代谢和转录途径的失调
  • 批准号:
    9170621
  • 财政年份:
    2016
  • 资助金额:
    $ 19.19万
  • 项目类别:
Novel therapies for cigarette smoke induced lung injury
香烟烟雾引起的肺损伤的新疗法
  • 批准号:
    8758419
  • 财政年份:
    2014
  • 资助金额:
    $ 19.19万
  • 项目类别:
Novel therapies for cigarette smoke induced lung injury
香烟烟雾引起的肺损伤的新疗法
  • 批准号:
    9066785
  • 财政年份:
    2014
  • 资助金额:
    $ 19.19万
  • 项目类别:
Environmental obesogens reduce Thy1 expression and promote obesity
环境致肥胖因素降低Thy1表达并促进肥胖
  • 批准号:
    8723204
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:
Aryl Hydrocarbon Receptor Ligands and Thyroid Eye Disease
芳基烃受体配体与甲状腺眼病
  • 批准号:
    9053494
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:
Aryl Hydrocarbon Receptor Ligands and Thyroid Eye Disease
芳基烃受体配体与甲状腺眼病
  • 批准号:
    8478945
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:
Aryl Hydrocarbon Receptor Ligands and Thyroid Eye Disease
芳基烃受体配体与甲状腺眼病
  • 批准号:
    8843871
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:
Naturally Occurring Lipid Mediators Enhance Antibody Production
天然存在的脂质介质增强抗体产生
  • 批准号:
    8428228
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:
Naturally Occurring Lipid Mediators Enhance Antibody Production
天然存在的脂质介质增强抗体产生
  • 批准号:
    8606727
  • 财政年份:
    2013
  • 资助金额:
    $ 19.19万
  • 项目类别:

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