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

异左旋黄素加合物在原发性高血压和系统性红斑狼疮中的作用

• 批准号: 10038920
• 负责人: David Patrick
• 金额: $ 15.84万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10038920
• 关键词: Angiotensin II; Animals; Antigen Presentation; Antigen-Presenting Cells; Aortitis; Attenuated; Autoantibodies; Autoantigens; Autoimmune Process; Biological Assay; Bone Marrow; Bortezomib; Cardiovascular Diseases; Cell surface; Cells; Characteristics; Clinical; Complex; Data; Dendritic Cells; Development; Disease; Essential Hypertension; Exhibits; Experimental Models; Fatty Acids; Fellowship; Flow Cytometry; Fluorescence Resonance Energy Transfer; Human; Hypertension; ITGAX gene; Immune Tolerance; Immunosuppression; Incidence; Inflammation; Kidney Diseases; Knowledge; Lupus; Lysine; MHC Class I Genes; Mentors; Modeling; Mus; Organ; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Plasma Cells; Population; Positioning Attribute; Process; Proteasome Inhibitor; Proteins; Publishing; Reactive Oxygen Species; Research; Role; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; To autoantigen; Transgenic Animals; Woman; adduct; autoreactive T cell; base; blood pressure reduction; career; chymotrypsin; conditional knockout; curative treatments; design; disease heterogeneity; experience; immune activation; inhibitor/antagonist; insight; monocyte; mouse model; multicatalytic endopeptidase complex; neoantigens; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; oxidation; patient subsets; peroxidation; prevent; recruit; response; systemic autoimmunity

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.

项目概要 原发性高血压和系统性红斑狼疮 (SLE) 是毁灭性的疾病。 尽管系统性红斑狼疮有多种治疗选择，但世界上仍有三分之一的人口患有高血压。 异质性疾病，其治疗仅限于使用非特异性整体免疫抑制。 人们对这些病症背后的机制缺乏了解。 由于这些分子加合物而形成的脂肪酸的氧化产物。 然后与蛋白质的赖氨酸残基共价结合，将加合的蛋白质作为自身抗原呈递给 T 细胞。 导致免疫细胞激活、高血压和系统性自身免疫。 研究和初步数据显示，很明显，原发性高血压和系统性红斑狼疮都是由这一过程引发的。 我发现了 isoLG 加合物的形成、加工和免疫细胞激活的重要作用。 免疫蛋白酶体在 isoLG 加合自身抗原的呈递、高血压的发展和 此外，我还在 SLE 小鼠模型中发现了主动脉炎症。 发现用 isoLG 清除剂 2-羟基苯甲胺治疗小鼠可以减轻高血压和 最后，我发现一部分 SLE 患者表现出 isoLG 积累。 抗原呈递细胞，表明这些细胞具有独特的临床特征和潜在的治疗机会 我认为在抗原呈递细胞内，isoLG 加合物是由一个处理和展示的。 此外，SLE 患者表现出 isoLG 加合物。 我的具体目标是：（1）确定 isoLG- 的作用。 (2) 确定角色 免疫蛋白酶体在 isoLG 抗原呈递和高血压中的功能 为了实现这些目标，我们将。 招募SLE患者并获取外周血单核细胞，将通过流式细胞术进行研究。 特定抗原呈递细胞群中存在 isoLG 加合物积累。 水平将与临床参数进行比较，以确定与加合物相关的特征 为了研究免疫蛋白酶体的功能，我将利用全面缺乏这三种酶的小鼠。 我还产生了免疫蛋白酶体亚基（TKO 小鼠）的条件敲除。 免疫蛋白酶体 (LMP7fl/fl) 的糜蛋白酶亚基，将与 CD11c-Cre 转基因杂交 动物产生抗原呈递细胞特异性LMP7缺陷动物将对这些动物进行研究。 在两个完善的获得性模型中高血压和炎症的发展 这些研究共同有望阐明小鼠原发性高血压的新机制。 此外，它们将为原发性高血压和 SLE 提供新的治疗机会。 治疗这些情况。