S100A9 and S100A8 in Diabetes and Atherosclerosis

描述（由申请人提供）：动脉粥样硬化引起的心血管并发症是1型糖尿病患者死亡的主要原因。在1型糖尿病小鼠模型中寻找糖尿病加速动脉粥样硬化的机制时，我们发现促炎蛋白S100 A9从糖尿病小鼠的巨噬细胞中以增加的水平分泌，并且免疫反应性S100 A9在糖尿病小鼠的动脉粥样硬化病变中丰富，并且与斑块内出血相关。有趣的是，最近的研究将S100 A9及其结合伴侣S100 A8确定为人类心血管事件的生物标志物。从患有1型糖尿病的人中分离的单核细胞表达高水平的S100 A9，提高了S100 A8/A9在糖尿病血管疾病中起重要作用的可能性。基于这些观察和初步研究，我们假设1型糖尿病促进组织中巨噬细胞的炎症群体，并且该群体分泌升高水平的S100 A8/A9。我们进一步假设S100 A8/A9通过两种机制促进1型糖尿病中的动脉粥样硬化：i）调节巨噬细胞活化状态;和ii）动脉壁中的局部炎症作用。将在分离的小鼠巨噬细胞、S100 A9缺陷小鼠和转基因LDL受体缺陷小鼠动脉粥样硬化模型（其中1型糖尿病可由病毒诱导）（LDLR-/-;GP小鼠）中进行拟定实验。我们建议直接测试S100 A8/A9在炎症和糖尿病加速动脉粥样硬化中的作用。目的是解决以下三个问题：1）1型糖尿病是否促进组织中炎症巨噬细胞的积累？2)S100 A8/A9是否调节1型糖尿病中的巨噬细胞活化？3)S100 A8/A9是否促进1型糖尿病病变的发生和/或进展？

DESCRIPTION (provided by applicant): Cardiovascular complications caused by atherosclerosis are the major cause of death in patients with type 1 diabetes. While searching for a mechanism of diabetes-accelerated atherosclerosis in a mouse model of type1diabetes, we discovered that the pro-inflammatory protein S100A9 is secreted at increased levels from macrophages from diabetic mice, and that immunoreactive S100A9 is abundant in atherosclerotic lesions from diabetic mice and correlates with intraplaque hemorrhage. Interestingly, recent studies identify S100A9 and its binding partner S100A8 as biomarkers of cardiovascular events in humans. Monocytes isolated from humans with type 1 diabetes express high levels of S100A9, raising the possibility that S100A8/A9 plays an important role in diabetic vascular disease. Based on these observations and preliminary studies, we hypothesize that type 1 diabetes promotes an inflammatory population of macrophages in tissues, and that this population secretes elevated levels of S100A8/A9. We further hypothesize that S100A8/A9 promotes atherosclerosis in type 1 diabetes by two mechanisms: i) regulation of macrophage activation state; and ii) local inflammatory effects in the artery wall. The proposed experiments will be carried out in isolated mouse macrophages, in an S100A9-deficient mouse, and in a transgenic LDL receptor-deficient mouse model of atherosclerosis in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). We propose to directly test the contribution of S100A8/A9 in inflammation and diabetes-accelerated atherosclerosis. The goal is to address the following three questions: 1) Does type 1 diabetes promote accumulation of inflammatory macrophages in tissues? 2) Does S100A8/A9 regulate macrophage activation in type 1 diabetes? 3) Does S100A8/A9 promote lesion initiation and/or progression in type 1 diabetes?