Leukocyte Regulation of Vascular Function

 描述（由申请人提供）： 目的：这项新应用的目标是阐明白细胞导致血管疾病的新机制，特别是在肥胖引发的低度炎症的情况下。肥胖背景下的血管疾病在美国退伍军人群体中极为常见。研究计划：为了评估中性粒细胞胞外陷阱（NET）对血管疾病的作用，将使用饮食诱导的肥胖和肥胖诱导的动脉粥样硬化的小鼠模型。体外模型将解决NET诱导的机制。设计用于抑制NET形成的疗法将用多个相关血管终点进行测试，包括内皮功能、血栓形成和动脉粥样硬化。最后，白细胞配体在介导导致NET形成的粘附相互作用中的作用将被确定，因为这可能作为上游治疗靶点。研究方法：实现这些目标的策略将是使用小鼠模型和体外测定来探索脂肪组织炎症的介质和与肥胖相关的血管风险。目的1将确定肥胖对中性粒细胞募集和脂肪组织库、骨髓和肥胖小鼠循环中性粒细胞中NET形成的影响。将进行体外实验，以确定肥胖脂肪组织成分对NET形成的影响，并考虑肥胖对骨髓源性中性粒细胞活化的全身影响。目的2将测试NET溶解或NET预防对肥胖加重的血管疾病终点的治疗效果，包括内皮功能、动脉粥样硬化和血栓形成。目的3将确定P-选择素糖蛋白配体-1（Psgl 1）对肥胖脂肪组织中性粒细胞募集和NET形成的贡献。

 DESCRIPTION (provided by applicant): Objectives: The goal of this new application is to elucidate novel mechanisms by which leukocytes contribute to vascular disease, particularly in the setting of the low grade inflammation triggered by obesity. Vascular disease in the setting of obesity is extremely common in the US veteran population. Research Plan: To assess the role of neutrophil extracellular traps (NETs) on vascular disease, mouse models of diet-induced obesity and obesity-induced atherosclerosis will be used. In vitro models will address the mechanisms by which NETs are induced. Therapies designed to inhibit NET formation will be tested with multiple relevant vascular endpoints, including endothelial function, thrombosis, and atherosclerosis. Finally, the role of a leukocyte ligand in mediating adhesive interactions resulting in NET formation will be determined as this may serve as an upstream therapeutic target. Methods: The strategy to accomplish the objectives will be to use mouse models and in vitro assays to explore mediators of adipose tissue inflammation and the vascular risk associated with obesity. Aim 1 will determine the effect of obesity on neutrophil recruitment and NET formation in adipose tissue depots, bone marrow, and circulating neutrophils from obese mice. In vitro experiments will be performed to determine the effect of obese adipose tissue components on NET formation and will consider the systemic effects of obesity on activation of bone marrow-derived neutrophils. Aim 2 will test the therapeutic effects of NET dissolution or NET prevention on vascular disease endpoints exacerbated by obesity, including endothelial function, atherosclerosis, and thrombosis. Aim 3 will determine the contribution of P-selectin glycoprotein ligand-1 (Psgl1) towards neutrophil recruitment and NET formation in obese adipose tissue.