Regulation of Adipose Tissue Inflammation by P-selectin Glycoprotein Ligand-1

描述（由申请人提供）： 摘要目的：本研究的目的是确定PSGL-1在介导内脏脂肪组织炎症中的作用。这些研究的结果可能会发现新的治疗靶点，以减少与肥胖流行病相关的血管合并症。研究计划：为了评估PSGL-1缺乏对内脏脂肪组织炎症发展的作用，将使用遗传和饮食诱导的肥胖症的小鼠模型。体外模型将解决PSGL-1调节内皮粘附分子表达的机制。最后，一种新的炎症性脂肪模型将用于确定PSGL-1在介导内脏炎症性脂肪对动脉粥样硬化的作用中的特异性作用。研究方法：实现这些目标的策略将是使用转基因小鼠模型和体外试验来探索脂肪炎症的介质和与炎症性脂肪相关的血管风险。目的1将确定PSGL-1缺乏对遗传和饮食诱导的肥胖小鼠模型中脂肪组织巨噬细胞浸润的影响。目的2将确定PSGL-1诱导肥胖患者内皮选择素和MCP-1表达的机制。目的3将确定PSGL-1中和对由炎性内脏脂肪组织诱导的动脉粥样硬化的影响。临床相关性：在美国退伍军人人群中，动脉粥样硬化是发病率和死亡率最常见的潜在原因。尽管一些靶向胆固醇的疗法被证明可用于预防动脉粥样硬化的并发症，如心肌梗死和中风，但这些并发症仍然很常见，并且由于肥胖症的流行，预计在不久的将来会增加。肥胖和血管风险之间的联系仍有待阐明，但最近的几项临床研究表明，内脏肥胖是肥胖相关的血管风险的主要原因。内脏脂肪组织是否是血管风险的标志物或介导物尚不清楚。肥胖的实验模型已经证明内脏脂肪和皮下脂肪在脂肪细胞因子表达和白细胞浸润方面存在显著差异。我们最近证明，在没有糖尿病的小鼠中，炎症性内脏脂肪组织足以加速动脉粥样硬化。因此，识别促进内脏脂肪炎症和/或介导与内脏脂肪炎症相关的血管风险增加的因素将有助于设计旨在降低与中心性肥胖相关的血管风险的疗法。对退伍军人医疗保健的潜在影响：通过揭示内脏肥胖影响血管疾病的机制，可以开发新的治疗方法，并应用于有动脉粥样硬化并发症风险的肥胖退伍军人人群。减少与血管疾病相关的发病率，如心肌梗死和中风，将对退伍军人的健康产生重大的有益影响。

DESCRIPTION (provided by applicant): Abstract Objectives: The goal of this proposal is to determine the role of PSGL-1 in mediating visceral adipose tissue inflammation. The results of these studies may uncover novel therapeutic targets to reduce the vascular comorbidities associated with the obesity epidemic. Research Plan: To assess the role of PSGL-1 deficiency on the development of visceral adipose tissue inflammation, mouse models of genetic and diet-induced obesity will be used. In vitro models will address the mechanisms by which PSGL-1 regulates endothelial adhesion molecule expression. Finally, a novel model of inflammatory fat will be used to determine the specific effect of PSGL-1 in mediating the effects of visceral inflammatory fat on atherosclerosis. Methods: The strategy to accomplish the objectives will be to use transgenic mouse models and in vitro assays to explore mediators of fat inflammation and the vascular risk associated with inflammatory fat. Aim 1 will determine the effect of PSGL-1 deficiency on adipose tissue macrophage infiltration in mouse models of genetic and diet-induced obesity. Aim 2 will determine mechanisms by which PSGL-1 induces expression of endothelial selectins and MCP-1 in obesity. Aim 3 will determine the effect of PSGL-1 neutralization on atherosclerosis induced by inflammatory visceral adipose tissue. Clinical Relevance: Atherosclerosis is the most common underlying cause of morbidity and mortality in the United States veteran population. Although some therapies targeting cholesterol are proving to be useful in preventing complications of atherosclerosis such as myocardial infarction and stroke, these complications are still commonplace and predicted to increase in the near future due to the obesity epidemic. Links between obesity and vascular risk remain to be elucidated, however several recent clinical studies have suggested that visceral adiposity is largely responsible for obesity-associated vascular risk. Whether visceral adipose tissue is a marker or mediator of vascular risk is unclear. Experimental models of obesity have demonstrated marked differences between visceral and subcutaneous fat in terms of adipocytokine expression and leukocyte infiltration. We have recently demonstrated that inflammatory visceral adipose tissue is sufficient to accelerate atherosclerosis in mice, in the absence of diabetes. Thus, identification of factors that promote visceral fat inflammation and/or mediate the increased vascular risk associated with visceral fat inflammation will be useful in designing therapies aimed at reducing the vascular risk associated with central obesity. Potential Impact on Veterans Health Care: By uncovering the mechanism(s) by which visceral adiposity affects vacular disease, new therapies can be developed and applied to the obese veteran population at risk for complications of atherosclerosis. Reducing the morbidities associated with vascular disease, such as myocardial infarction and stroke, will have a major beneficial effect on the health of the veteran population.