Role of extracellular vesicles in the regulation of immunometabolism in obesity

项目摘要/摘要 肥胖症在世界范围内的流行已经达到了大流行的程度。肥胖有很强的炎症性 与慢性炎症性疾病的发展有关的基础，包括 阿尔茨海默病(AD)。然而，肥胖引发反常炎症的机制是 没有明确的定义。 肥胖性肝骨病常伴有肝脏胰岛素抵抗， 随后导致高胰岛素血症。在我们的母公司R01研究中，我们的目标是证明在肥胖症中， 高胰岛素血症促进促炎细胞外小泡(EVS)的生物发生和分泌 电动汽车会引起反常的炎症。在本行政副刊(NOT-AG-20-034)中，我们建议 应用我们的研究结果和实验工具探讨AD的发病机制。 炎症性电动车。我们假设，在肥胖中，EVS会变得促炎并导致异常 甚至在大脑中的炎症反应，这有助于AD的发展。 最近的证据表明，肝功能在阿尔茨海默病的病理生理学中起着重要作用。 因此，我们推测肥胖和高胰岛素血症下的H-EVS参与了AD的病理生理过程。这些 初步结果提示：(1)在高胰岛素血症的发生过程中，肝细胞 分泌病理的、促炎的EV，以及(2)这些促炎的EV被体内的细胞摄取 导致脑部异常发炎。为了测试这一点，我们将实现以下目标： 这项提案中的研究将：(1)确定EV在大脑中的受体细胞及其炎症 以及(2)确定载脂蛋白E基因变异在EVS促炎特性中的作用。本研究 将是解决这些悬而未决的问题的关键一步，即肥胖和高胰岛素血症 与阿尔茨海默病的发展相关，寻找潜在的防治靶点 人体内的广告。

Project Abstract/Summary The worldwide prevalence of obesity has reached pandemic proportions. Obesity has strong inflammatory underpinnings, which are associated with the development of chronic inflammatory diseases, including Alzheimer’s disease (AD). However, the mechanisms by which obesity provokes aberrant inflammation are not clearly defined. Obesity-induced hepatosteatosis is frequently accompanied by hepatic insulin resistance, subsequently causing hyperinsulinemia. In our parent R01 study, we aim to demonstrate that in obesity, hyperinsulinemia enhances the biogenesis and secretion of pro-inflammatory extracellular vesicles (EVs) and that EVs cause aberrant inflammation. In this Administrative Supplements (NOT-AG-20-034), we propose to investigate the pathogenesis of AD by applying our findings and experimental tools used in researching pro- inflammatory EVs. We hypothesize that in obesity, EVs become pro-inflammatory and induces abnormal inflammatory responses even in the brain, which contribute to the development of AD. As recent evidence suggests, an important role of liver function is in the pathophysiology of AD, and so we hypothesize that H-EVs under obesity and hyperinsulinemia mediate the pathophysiology of AD. These preliminary results led us to the hypotheses: (1) during the development of hyperinsulinemia, hepatocytes secrete pathologic, pro-inflammatory EVs, and (2) these pro-inflammatory EVs are uptaken by cells in the brain leading to aberrant inflammation. To test this, we will pursue the following Aims: Studies in this proposal will: (1) determine recipient cells of EVs in the brain and their inflammatory status, and (2) determine the role of APOE genetic variants in the pro-inflammatory traits of EVs. This study would be a critical step addressing these unsolved questions of how obesity and hyperinsulinemia are associated with the development of AD and identifying potential therapeutic targets for preventing and treating AD in humans.