Establish a novel mouse model tracking multiple extracellular vesicles

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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.