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目标，以减少与肥胖流行相关的血管并发症。研究计划：为了评估PSGL-1缺乏在内脏脂肪组织炎症发展中的作用，将使用遗传和饮食诱导的肥胖小鼠模型。体外模型将探讨PSGL-1调节内皮细胞黏附分子表达的机制。最后，将使用一种新的炎性脂肪模型来确定PSGL-1在介导内脏炎性脂肪对动脉粥样硬化影响中的特异性作用。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性脂肪相关的血管风险。目的1研究PSGL-1缺乏对遗传性肥胖和饮食诱导肥胖小鼠脂肪组织巨噬细胞浸润的影响。目的2探讨PSGL-1诱导肥胖症患者血管内皮细胞选择素和单核细胞趋化蛋白-1表达的机制。目的3确定PSGL-1中和对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：动脉粥样硬化是美国退伍军人中发病率和死亡率最常见的潜在原因。尽管一些针对胆固醇的疗法被证明在预防动脉粥样硬化并发症(如心肌梗死和中风)方面有用，但这些并发症仍然很常见，预计在不久的将来由于肥胖的流行还会增加。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，内脏肥胖症在很大程度上与肥胖相关的血管风险有关。内脏脂肪组织是血管风险的标志物还是中介物尚不清楚。肥胖的实验模型显示，内脏脂肪和皮下脂肪在脂肪细胞因子表达和白细胞渗透方面存在显著差异。我们最近证明，在没有糖尿病的情况下，炎性内脏脂肪组织足以加速小鼠的动脉粥样硬化。因此，确定促进内脏脂肪炎症和/或调节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(S)，可以开发新的治疗方法，并将其应用于面临动脉粥样硬化并发症风险的肥胖退伍军人群体。减少与血管疾病相关的发病率，如心肌梗塞和中风，将对退伍军人的健康产生重大有益影响。 公共卫生相关性： 项目简介肥胖在美国很流行，对心血管疾病的发病率和死亡率有不利影响。最近的临床研究表明，与肥胖相关的大血管风险是由于内脏过度肥胖所致。我们的假设是，脂肪中的炎症是肥胖相关血管风险的罪魁祸首。识别脂肪炎症的细胞和分子介质可能导致旨在降低超重人群中心肌梗死和中风风险的新型治疗药物。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Obesity is epidemic in the US and having an adverse impact on cardiovascular morbidity and mortality. Recent clinical studies have demonstrated that the macrovascular risk associated with obesity is due to excess visceral adiposity. Our hypothesis is that inflammation in fat is responsible for the vascular risk associated with obesity. Identification of the cellular and molecular mediators of fat inflammation may lead to novel therapeutic agents aimed at reducing the risk of myocardial infarction and stroke in an overweight population.