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

项目摘要 原发性高血压和系统性红斑狼疮（SLE）是毁灭性的条件。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 异质性疾病，其治疗仅限于使用非特异性整体免疫抑制。 人们对这些疾病的机制缺乏了解。异evuglandins（IsoLG）是 由活性氧形成的脂肪酸的氧化产物。这些分子加合 与蛋白质的赖氨酸残基共价连接。加合的蛋白质然后作为自身抗原呈递给T细胞 导致免疫细胞活化、高血压和系统性自身免疫。根据此前发布的 研究和初步数据表明，原发性高血压和SLE都是由这一过程引起的， 异LG-加合物形成、加工和免疫细胞活化。我发现了 免疫蛋白酶体在异LG-加合自身抗原呈递、高血压发生和 原发性高血压小鼠模型的主动脉炎症。此外，在SLE小鼠模型中，我还 发现用异LG清除剂2-羟基苄胺治疗小鼠，可以减轻高血压， 系统性自身免疫最后，我发现SLE患者的一个子集表现出异LG积累， 抗原提呈细胞，这表明了独特的临床概况和潜在的治疗机会，这些 患者我假设在抗原呈递细胞内，异LG加合物是由一个 免疫蛋白酶体依赖机制。此外，表现出异LG-加合物的SLE患者 积累表现出独特的疾病特征。具体目的是：（1）确定异LG的作用; SLE相关高血压和疾病异质性的加合物。(2)确定的作用 免疫蛋白酶体在异LG抗原呈递和高血压中功能。为了实现这些目标，我们将 招募SLE患者并获得外周血单个核细胞。将通过流式细胞术研究细胞， 在抗原呈递细胞的特定群体内存在异LG-加合物积累。异LG加合物 将水平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，我将利用三种免疫蛋白酶体缺陷的小鼠， 免疫蛋白酶体的亚基（TKO小鼠）。我还生成了一个条件性敲除 免疫蛋白酶体的胰凝乳蛋白酶亚基（LMP 7 fl/fl），其将与CD 11 c-Cre转基因杂交 动物以产生抗原呈递细胞特异性LMP 7缺陷动物。这些动物将被研究， 高血压和炎症的发展，在两个良好建立的后天模型的设置， 小鼠原发性高血压。总之，这些研究有希望阐明新的机制， 对原发性高血压和SLE的见解。此外，它们将为糖尿病患者提供新的治疗机会。 这些条件的治疗。

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.