Establish a novel mouse model tracking multiple extracellular vesicles

建立追踪多个细胞外囊泡的新型小鼠模型

• 批准号: 10288370
• 负责人: Takahisa Nakamura
• 金额: $ 23.85万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-16 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288370
• 关键词: Adipose tissue; Adolescent obesity; Alzheimer' s Disease; Attention; CRISPR/Cas technology; Caliber; Cardiovascular Diseases; Cells; Characteristics; Chronic; Coupled; Destinations; Development; Disease; Distant; Exhibits; Extracellular Space; Health; Hepatic; Hepatocyte; Inflammation; Inflammatory; Knockout Mice; Knowledge; Label; Lead; Liver; Malignant Neoplasms; Mediating; Membrane; Metabolic; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Pathogenesis; Pathogenicity; Peripheral Blood Mononuclear Cell; Physiological; Process; Proteins; RNA; RNA-Induced Silencing Complex; Regulation; Research; Risk Factors; Role; Skeletal Muscle; Solid; Spleen; Techniques; Thinness; Tissues; Transducers; Transgenic Mice; United States National Institutes of Health; bariatric surgery; cell type; chronic inflammatory disease; diet-induced obesity; exosome; extracellular vesicles; immune function; in vivo; intercellular communication; macrophage; mouse model; nanosized; novel; pathogen; response; tool; trait; vesicular release; Adipose tissue; Adolescent obesity; Alzheimer' s Disease; Attention; CRISPR/Cas technology; Caliber; Cardiovascular Diseases; Cells; Characteristics; Chronic; Coupled; Destinations; Development; Disease; Distant; Exhibits; Extracellular Space; Health; Hepatic; Hepatocyte; Inflammation; Inflammatory; Knockout Mice; Knowledge; Label; Lead; Liver; Malignant Neoplasms; Mediating; Membrane; Metabolic; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Organ; Pathogenesis; Pathogenicity; Peripheral Blood Mononuclear Cell; Physiological; Process; Proteins; RNA; RNA-Induced Silencing Complex; Regulation; Research; Risk Factors; Role; Skeletal Muscle; Solid; Spleen; Techniques; Thinness; Tissues; Transducers; Transgenic Mice; United States National Institutes of Health; bariatric surgery; cell type; chronic inflammatory disease; diet-induced obesity; exosome; extracellular vesicles; immune function; in vivo; intercellular communication; macrophage; mouse model; nanosized; novel; pathogen; response; tool; trait; vesicular release

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.

项目摘要 促炎的过程，尤其是导致慢性感染的过程，已暗示 肥胖症，这是多种疾病的危险因素，包括2型糖尿病（T2D），心血管 疾病（CVD）和阿尔茨海默氏病（AD）和癌症。但是，促进的机制 炎症过程被引起，导致慢性炎症性疾病没有明确定义。 最近的研究表明，膜封闭的细胞外蔬菜（EV），包括纳米化 外泌体（直径为30-150 nm），充当细胞间通信的关键传感器 涉及慢性炎症性疾病的炎症调节。因此，阐明 电动汽车在控制促炎过程中的作用对于更好地了解 这些疾病的发病机理。 为了分析疾病状况中电动汽车的分析，对体内工具的迫切需要 跟踪特定电动汽车的起源和目的地，这将使我们能够调查体内网络 细胞/组织特异性EV及其对受体细胞特征的影响。但是，缺乏这种体内 工具限制了我们在慢性炎症性疾病中执行靶向EV分析的能力。克服这一点 限制并理解这些疾病中EV介导的炎症调节，我们旨在发展 新的小鼠模型通过利用我们的 生成转基因鼠标线的专业知识和开始技术。使用这些鼠标模型，我们将 研究从单个小鼠中的多个代谢组织中的EV的体内网络 慢性炎症性疾病的发病机理，直接反应NIH公告PAR-19-369。 该提案中的研究将：（1）建立可以监视从三个分泌的电动汽车的鼠标模型 单个小鼠中的主要代谢细胞，（2）检查这些EV的炎症性状 通过分析新的小鼠模型，炎症状态。通过使用我们的新鼠标模型与我们的 调查电动汽车炎症性状的系统方法，我们将揭示如何的新机制 三个主要的代谢细胞有助于慢性炎性疾病的发展。