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达到大流行的程度。肥胖具有强烈的炎症性 基础，这是与慢性炎症性疾病的发展，包括 阿尔茨海默病（AD）。然而，肥胖引起异常炎症的机制是 没有明确定义。 肥胖引起的脂肪肝常伴有肝胰岛素抵抗， 随后引起高胰岛素血症。在我们的R 01研究中，我们的目标是证明在肥胖症中， 高胰岛素血症增强促炎性细胞外囊泡（EV）的生物发生和分泌， 电动汽车会导致异常炎症在本管理补充文件（NOT-AG-20-034）中，我们建议： 应用我们的发现和实验工具研究AD的发病机制， 炎性EV。我们假设，在肥胖症中，EV成为促炎性物质，并诱导异常 炎症反应甚至在大脑中，这有助于AD的发展。 最近的证据表明，肝功能在AD的病理生理学中起重要作用， 因此，我们假设肥胖和高胰岛素血症下的H-EV介导AD的病理生理学。这些 初步结果使我们提出以下假设：（1）在高胰岛素血症的发展过程中， 分泌病理性的促炎EV，和（2）这些促炎EV被组织中的细胞摄取， 导致异常炎症为了验证这一点，我们将追求以下目标： 本研究将：（1）确定脑内EV的受体细胞及其炎症反应， 状态，和（2）确定载脂蛋白E遗传变异体在EV促炎性状中的作用。本研究 将是解决肥胖和高胰岛素血症是如何 与AD的发展相关，并确定预防和治疗AD的潜在治疗靶标 人类AD

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.