Exosomes in the Pathogenesis of Diabetic Atherosclerosis & its Treatment Opportunities

外泌体在糖尿病动脉粥样硬化发病机制中的作用

基本信息

  • 批准号:
    10477275
  • 负责人:
  • 金额:
    --
  • 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:
    2019-07-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

The goal of this proposal is to understand why people with diabetes develop severe fatty-rich plaques called atherosclerosis in arteries. Accelerated atherosclerosis has been linked to several types of cardiovascular diseases that cause disabilities and premature death amongst diabetic individuals. Unfortunately, such serious medical problems are very frequent among veterans enrolled in the VHA Health Care System as they are almost three times more likely to develop diabetes than people in the general population. One reason that has been identified to enhance atherosclerosis among diabetic individuals is high blood sugar, also called “hyperglycemia”. But exactly how hyperglycemia enhances atherosclerosis is not known. Our recent research focus has centered on exploring the role of microvesicles released by cells, called “exosomes”, as a source of inflammation in atherosclerosis. Preliminary findings presented in our revised grant proposal show that human diabetic subjects diagnosed with advance peripheral atherosclerotic cardiovascular disease accumulate pro-inflammatory exosomes in their bloodstream. Our findings also show that diabetic mice accumulate pro-inflammatory exosomes in their bloodstream. Furthermore, our findings show that such diabetic plasma exosomes can increase the number of white blood cells that accumulate in arteries when they are infused into non-diabetic mice. Interestingly, our data demonstrate that pro-inflammatory exosomes can be produced by macrophages cultured in glucose-rich medium that simulates diabetic hyperglycemia. Remarkably, our data also show that macrophages can produce anti-inflammatory exosomes when they cultured in medium that contains protective cytokines such as interleukin-4. Based on our extensive new findings, we propose to explore whether diabetic hyperglycemia enhances the progression of atherosclerosis through exosomes that communicate pro-inflammatory signaling in the immune system and the vessel wall. We also aim to produce exosomes that can serve to overcome the effects of hyperglycemia to suppress the progression of diabetic atherosclerosis. In our First Aim we will define the extent to which hyperglycemia causes the production of proinflammatory exosomes in the bloodstream of veterans suffering from advanced atherosclerotic disease. We will do the same by studying mouse models of diabetes. Next, we will test the ability of diabetic plasma exosomes to enhance vascular inflammation and atherosclerosis when infused into hyperlipidemic mice. We will also test whether macrophages cultured in medium that contains elevated levels of glucose or bad cholesterol called oxLDL, will produce exosomes that can induce atherosclerosis when infused into non-diabetic mice. Lastly, we will explore if a class of signaling molecule called microRNA carried by exosomes are responsible for their inflammatory signaling. In our Second Aim we will seek to produce therapeutic exosomes. Our strategy will consist of isolating exosomes from macrophages cultured in medium that contains protective factors including interleukin-4. Our second strategy will be to produce bioengineered exosomes from cultured macrophage tailored to produce desired levels of protective miRNA and test whether such exosomes can exert anti-inflammatory properties to reduce the progression of atherosclerosis in diabetic mice.
这项提案的目标是了解为什么糖尿病患者会出现严重的富含脂肪的斑块,称为 动脉粥样硬化。加速的动脉粥样硬化与几种类型的心血管疾病有关 在糖尿病患者中导致残疾和过早死亡的疾病。不幸的是,如此严重的 在参加VHA医疗保健系统的退伍军人中,医疗问题非常频繁,因为他们几乎 患糖尿病的可能性是普通人群的三倍。其中一个原因是 高血糖也被称为“高血糖”,是导致糖尿病患者动脉粥样硬化的主要原因。 但目前尚不清楚高血糖是如何促进动脉粥样硬化的。 我们最近的研究重点是探索细胞释放的微泡的作用,称为 “外切体”,作为动脉粥样硬化中炎症的来源。我们修订后的拨款中提出了初步研究结果 建议人类糖尿病受试者被诊断为晚期外周动脉粥样硬化性心血管疾病 疾病会在他们的血液中积聚促炎症的外切体。我们的发现还表明,糖尿病小鼠 在他们的血液中积聚促炎症的外切体。此外,我们的研究结果表明,这种糖尿病 血浆外切体可以增加动脉中积聚的白细胞的数量 转化为非糖尿病小鼠。有趣的是,我们的数据表明,促炎外切体可以通过 巨噬细胞在模拟糖尿病高血糖的富葡萄糖培养液中培养。值得注意的是,我们的数据还 显示巨噬细胞在含有以下物质的培养液中培养时可以产生抗炎外切体 保护性细胞因子,如白介素4。 基于我们广泛的新发现,我们建议探索糖尿病高血糖是否会增强 免疫中传递促炎信号的外切体在动脉粥样硬化中的进展 系统和管壁。我们的目标也是生产能够帮助克服 高血糖抑制糖尿病动脉粥样硬化的进展。 在我们的第一个目标中,我们将定义高血糖导致促炎反应的程度。 患有晚期动脉粥样硬化性疾病的退伍军人血液中的外切体。我们也会这么做的 通过研究糖尿病的小鼠模型。接下来,我们将测试糖尿病患者血浆外切体增强的能力 给高脂血症小鼠注射血管炎症和动脉粥样硬化。我们还将测试 巨噬细胞在含有高水平葡萄糖或坏胆固醇的培养液中培养,称为oxLDL,将 当注射到非糖尿病小鼠体内时,产生可导致动脉粥样硬化的外切体。最后,我们将探索 如果外周小体携带的一类称为microRNA的信号分子对它们的炎症负责 发信号。 在我们的第二个目标中,我们将寻求生产治疗性外显体。我们的战略将包括孤立 巨噬细胞在含有包括白介素4在内的保护性因子的培养液中培养的外切体。我们的 第二个策略将是从培养的巨噬细胞中生产生物工程外切体,以生产 所需的保护性miRNA水平,并测试这些外切体是否可以发挥抗炎特性 减少糖尿病小鼠动脉粥样硬化的进展。

项目成果

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Robert Raffai其他文献

Robert Raffai的其他文献

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{{ truncateString('Robert Raffai', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10618158
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10373040
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Exosomes in the Pathogenesis of Diabetic Atherosclerosis & its Treatment Opportunities
外泌体在糖尿病动脉粥样硬化发病机制中的作用
  • 批准号:
    10266066
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Hyperglycemia and MicroRNA Dysregulation of Inflammation in Atherosclerosis
高血糖和动脉粥样硬化炎症的 MicroRNA 失调
  • 批准号:
    9159905
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?
糖尿病高血糖是否调节动脉粥样硬化的进展和消退?
  • 批准号:
    7904122
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Role of apolipoprotein E4 in the progression and regression of atherosclerosis
载脂蛋白E4在动脉粥样硬化进展和消退中的作用
  • 批准号:
    7839017
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?
糖尿病高血糖是否调节动脉粥样硬化的进展和消退?
  • 批准号:
    8397520
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?
糖尿病高血糖是否调节动脉粥样硬化的进展和消退?
  • 批准号:
    7797240
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?
糖尿病高血糖是否调节动脉粥样硬化的进展和消退?
  • 批准号:
    8195896
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
Role of apolipoprotein E4 in the progression and regression of atherosclerosis
载脂蛋白E4在动脉粥样硬化进展和消退中的作用
  • 批准号:
    7642511
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:

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瑞芬太尼对挥发性麻醉药所致心肌保护及抗炎作用的影响
  • 批准号:
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