A Role of Isolevuglandin Adducts in Essential Hypertension and Systemic Lupus Erythematosus

项目总结 高血压和系统性红斑狼疮(SLE)是毁灭性的疾病。估计有一个- 尽管有大量的治疗选择，但世界上三分之一的人口患有高血压。SLE是一种 异质性疾病，其治疗仅限于使用非特异性的全球免疫抑制。 对这些情况背后的机制缺乏了解。Isolevuglandins(IsoLGs)是 脂肪酸的氧化产物，是由活性氧物种形成的。这些分子加成了 与蛋白质的赖氨酸残基共价。然后将加合物蛋白作为自身抗原呈递给T细胞 导致免疫细胞激活、高血压和全身自身免疫。基于之前发布的 研究和初步数据表明，原发性高血压和系统性红斑狼疮都是由这一过程启动的 等LG-加合物的形成、加工和免疫细胞的激活。我发现了一个重要的角色 免疫蛋白酶体与等LG加合物自身抗原的呈递、高血压的发生、以及 高血压病小鼠模型中的主动脉炎症。此外，在系统性红斑狼疮的小鼠模型中，我还 发现用等低密度脂蛋白清除剂2-羟基苯甲胺治疗小鼠，可以降低高血压和 全身性自身免疫。最后，我发现SLE患者的一个子集在 抗原提呈细胞，提示了这些疾病独特的临床特征和潜在的治疗机会 病人。我假设在抗原提呈细胞中，等LG加合物是由一种 免疫蛋白酶体依赖机制。此外，表现出等LG加合物的SLE患者 积聚表现出独特的病害特征。我的具体目标是：(1)确定ISO-LG的角色- 与系统性红斑狼疮相关的高血压和疾病异质性的加合物。(二)确定党的作用 免疫蛋白酶体在Isolg抗原提呈和高血压中的作用。为了实现这些目标，我们将 招募系统性红斑狼疮患者，获取外周血单核细胞。将通过流式细胞术对细胞进行研究 在特定的抗原提呈细胞群体中存在等Lg加合物的积聚。等LG-加合物 水平将与临床参数进行比较，以确定与加合物相关的特征。 积累。为了研究免疫蛋白酶体的功能，我将利用全球范围内缺乏这三种蛋白质的小鼠。 免疫蛋白酶体的亚单位(TKO小鼠)。我还生成了一个有条件的淘汰赛 与CD11c-Cre转基因杂交的免疫蛋白酶体胰凝乳蛋白酶亚基(LMP7fl/fl) 动物产生抗原提呈细胞特异性的LMP7缺陷动物。这些动物将被研究 高血压和炎症在两种公认的获得性高血压模型的背景下的发展 小鼠的原发性高血压。总而言之，这些研究有望阐明新的机制。 对原发性高血压和系统性红斑狼疮的洞察。此外，它们还将提供新的治疗机会 这些病症的治疗。

PROJECT SUMMARY Essential hypertension and systemic lupus erythematosus (SLE) are devastating conditions. An estimated one- third of the world’s population suffers from hypertension despite a large number of treatment options. SLE is a heterogeneous disease the treatment of which is limited to the use of non-specific global immunosuppression. There is a lack of understanding of the mechanisms underlying these conditions. Isolevuglandins (IsoLGs) are oxidation products of fatty acids that form as a result of reactive oxygen species. These molecules adduct covalently to lysine residues of proteins. Adducted proteins are then presented as autoantigens to T-cells resulting in immune cell activation, hypertension, and systemic autoimmunity. Based upon previously published studies and preliminary data, it is clear that both essential hypertension and SLE are initiated by this process of isoLG-adduct formation, processing, and immune cell activation. I have discovered an important role of the immunoproteasome in the presentation of isoLG-adducted autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential hypertension. Moreover, in a mouse model of SLE, I have also discovered that treatment of mice with an isoLG scavenger, 2-hydroxybenzylamine, attenuates hypertension and systemic autoimmunity. Finally, I found that a subset of patients with SLE exhibit isoLG accumulation within antigen presenting cells, suggesting a unique clinical profile and potential therapeutic opportunities for these patients. I hypothesize that within antigen presenting cells, isoLG adducts are processed and displayed by an immunoproteasome dependent mechanism. Additionally, patients with SLE that exhibit isoLG-adduct accumulation exhibit unique disease characteristics. My specific aims are: (1) To determine a role of isoLG- adducts in SLE-associated hypertension and disease heterogeneity. (2) To determine the role of immunoproteasome function in isoLG antigen presentation and hypertension. To accomplish these aims we will recruit SLE patients and obtain peripheral blood mononuclear cells. Cells will be studied by flow cytometry for the presence of isoLG-adduct accumulation within specific populations of antigen presenting cells. IsoLG-adduct levels will be compared with clinical parameters to determine the characteristics that correlate with adduct accumulation. To study the function of the immunoproteasome, I will utilize mice globally deficient for the three subunits of the immunoproteasome (TKO mice). I have also generated a conditional knockout of the chymotrypsin subunit of the immunoproteasome (LMP7fl/fl) which will be crossed to CD11c-Cre transgenic animals to generate an antigen presenting cell specific LMP7 deficient animal. These animals will be studied for the development of hypertension and inflammation in the setting of two well established acquired models of essential hypertension in mice. Together, these studies hold the promise of elucidating novel mechanistic insights into essential hypertension and SLE. Moreover, they will provide novel therapeutic opportunities for the treatment of these conditions.