Establish a novel mouse model tracking multiple extracellular vesicles

项目摘要 促炎过程，特别是那些导致慢性炎症的过程，已经涉及到 肥胖是许多疾病的风险因素，包括2型糖尿病（T2 D）、心血管疾病和糖尿病。 疾病（CVD）和阿尔茨海默病（AD）和癌症。然而，亲- 炎症过程被激发并导致慢性炎症性疾病尚未明确定义。 最近的研究表明，膜封闭的细胞外囊泡（EV），包括纳米尺寸的囊泡， 外泌体（直径30-150 nm），作为细胞间通讯的关键转换器， 炎症调节参与慢性炎症性疾病的发展。因此，阐明 EV在调节促炎过程中的作用对于更好地理解 这些疾病的发病机制。 对于疾病状况中EV的分析，迫切需要可以选择性地分析EV的体内工具。 追踪特定电动汽车的起源和目的地，这将使我们能够研究体内的网络， 细胞/组织特异性EV及其对受体细胞特性的影响。然而，缺乏这样的体内 工具限制了我们在慢性炎症性疾病中进行靶向EV分析的能力。为了克服这个 限制和理解这些疾病中EV介导的炎症调节，我们的目标是开发 新的小鼠模型，以研究从三个主要代谢细胞分泌的EV，利用我们的 在产生转基因小鼠品系方面的专业知识和最新技术。有了这些小鼠模型，我们将 研究来自单个小鼠内多个代谢组织的EV的体内网络， 慢性炎症性疾病的发病机制，直接响应NIH公告PAR-19-369。 本课题的主要研究内容如下：（1）建立小鼠模型，监测三种肠病毒的分泌; 在单个小鼠中的主要代谢细胞，和（2）检查慢性炎症中这些EV的炎症特征。 通过分析新的小鼠模型来观察炎症状态。通过利用我们的新小鼠模型， 系统的方法研究EV的炎症特征，我们将揭示新的机制， 三种主要的代谢细胞促成慢性炎性疾病的发展。

Project Summary Pro-inflammatory processes, particularly those resulting in chronic inflammation, have been implicated in obesity, which is the risk factor for numerous diseases, including type 2 diabetes (T2D), cardiovascular disease (CVD), and Alzheimer’s disease (AD), and cancer. However, the mechanisms by which pro- inflammatory processes are provoked and lead to chronic inflammatory diseases are not clearly defined. Recent studies have revealed that membrane-enclosed extracellular vesicles (EVs), including nanosized exosomes (30–150 nm in diameter), function as crucial transducers of intercellular communication for inflammatory regulation involved in the development of chronic inflammatory diseases. Therefore, elucidating the role of EVs in regulating pro-inflammatory processes would be of importance to better understand the pathogenesis of these diseases. For the analysis of EVs in disease conditions, there is a critical need for in vivo tools that can selectively track the origin and destination of specific EVs, which would allow us to investigate the in vivo networks of cell/tissue-specific EVs and their impact on characteristics of recipient cells. However, the lack of such in vivo tools limits our ability to perform targeted EV analysis in chronic inflammatory diseases. To overcome this limitation and comprehend the EV-mediated inflammatory regulation in these diseases, we aim to develop new mouse models to investigate EVs secreted from three major metabolic cells by taking advantage of our expertise and start-of-art techniques in generating transgenic mouse lines. With these mouse models, we will investigate the in vivo networks of EVs from multiple metabolic tissues within a single mouse during the pathogenesis of chronic inflammatory diseases, in direct response to the NIH announcement PAR-19-369. Studies in this proposal will: (1) Establish mouse models that can monitor EVs secreted from three major metabolic cells in a single mouse, and (2) Examine inflammatory traits of these EVs in the chronic inflammatory state by analyzing the new mouse models. By utilizing our new mouse models coupled with our systematic approaches investigating the inflammatory traits of EVs, we will reveal novel mechanisms of how three major metabolic cells contribute to the development of chronic inflammatory diseases.