Leukocyte Regulation of Vascular Function

 描述(由申请人提供)： 目的：这一新应用的目的是阐明白细胞促进血管疾病的新机制，特别是在肥胖引发的低级别炎症的背景下。肥胖背景下的血管疾病在美国退伍军人中非常常见。研究计划：为了评估中性粒细胞细胞外陷阱(NETs)在血管疾病中的作用，将使用饮食诱导肥胖和肥胖诱导动脉粥样硬化的小鼠模型。体外模型将解决Net被诱导的机制。旨在抑制网络形成的疗法将在多个相关的血管终点进行测试，包括内皮功能、血栓形成和动脉粥样硬化。最后，将确定白细胞配体在调节黏附相互作用中的作用，从而导致网络形成，因为这可能作为上游治疗靶点。方法：实现这些目标的策略将是使用小鼠模型和体外试验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确定肥胖对肥胖小鼠脂肪组织、骨髓和循环中中性粒细胞募集和网络形成的影响。体外实验将确定肥胖脂肪组织成分对网络形成的影响，并将考虑肥胖对骨髓来源的中性粒细胞激活的全身影响。目的2将测试净溶解或净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确定P-选择素糖蛋白配体-1(Psgl1)在肥胖脂肪组织中性粒细胞募集和网状形成中的作用。

 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.