A Role of Isolevuglandins in Essential Hypertension and Systemic Lupus Erythematosus

异黄兰素在原发性高血压和系统性红斑狼疮中的作用

• 批准号: 10513285
• 负责人: David Patrick
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513285
• 关键词: Affect; Angiotensin II; Animals; Antigen Presentation; Antigen-Presenting Cells; Aortitis; Attenuated; Autoantibodies; Autoantigens; Autoimmune Diseases; Biological Assay; Bone Marrow; Bortezomib; CRISPR/Cas technology; Cardiovascular Diseases; Cause of Death; Cell surface; Cells; Characteristics; Chemical Models; Chemicals; 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; Immune Tolerance; Immunosuppression; Incidence; Inflammation; Injury to Kidney; Kidney Diseases; Knowledge; Ligation; Lupus; Lysine; MHC Class I Genes; Mentors; Minority; Modeling; Mus; Mutant Strains Mice; Organ; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Plasma Cells; Population; Positioning Attribute; Pristane; Process; Production; Proteasome Inhibitor; Proteins; Publishing; Reactive Oxygen Species; Research; Role; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Therapeutic; Tissues; Transgenic Animals; United States; Veterans; Woman; adduct; autoimmune pathogenesis; autoreactive T cell; blood pressure reduction; cardiovascular risk factor; career; chymotrypsin; conditional knockout; curative treatments; design; disease heterogeneity; experience; hypertensive; immune activation; inhibitor; insight; migration; 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 for United States Veterans. 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 and resultant 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 subunit LMP7 in the presentation of isoLG-adducted autoantigens, the development of hypertension, and aortic inflammation in a mouse model of essential hypertension. Additionally, in a mouse model of SLE, I have also discovered that treatment 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 in both hypertension and SLE, isoLG adducts are processed and displayed by an immunoproteasome dependent mechanism with a primary role of the immunoproteasome subunit LMP7. 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-adducted antigen presentation and hypertension. (3) To determine the role of LMP7 function in immune activation, isoLG-adducted antigen presentation, and hypertension in SLE. 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 unique populations of antigen presenting cells. IsoLG-adduct levels will be compared with clinical parameters to determine the parameters 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. To study the role of LMP7 in SLE, I propose to examine the effect of the LMP7 inhibitor PR-957 in the B6.SLE123 murine model of SLE. Additionally, I will study the effect of dendritic cell specific LMP7 deletion in a model of chemically-induced SLE by treating LMP7fl/fl/CD11c-Cre with pristane. Animals will be studied for the development of hypertension, immune cell expansion, autoantibody production, and renal injury. 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) 对美国来说是毁灭性的疾病 尽管有大量退伍军人，但估计世界上有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药物。 对这些病症背后的机制缺乏了解。 异黄兰素 (IsoLG) 是由于活性氧而形成的脂肪酸的氧化产物。 这些分子与蛋白质的赖氨酸残基共价加合，然后将加合蛋白质表示为。 T 细胞的自身抗原导致免疫细胞激活并导致高血压和全身性自身免疫。 根据之前发表的研究和初步数据，很明显，原发性高血压和 SLE 是由 isoLG 加合物形成、加工和免疫细胞激活的过程引发的。 发现免疫蛋白酶体亚基 LMP7 在 isoLG 加合的呈递中发挥重要作用 自身抗原、高血压的发生和小鼠模型中的主动脉炎症 此外，在 SLE 小鼠模型中，我还发现使用 isoLG 进行治疗。 清除剂，2-羟基苄胺，可以减轻高血压和全身性自身免疫。 SLE 患者的子集在抗原呈递细胞内表现出 isoLG 积累，这表明存在独特的 这些患者的临床概况和潜在的治疗机会。 高血压和 SLE 中的呈递细胞，isoLG 加合物由一个 免疫蛋白酶体依赖机制，免疫蛋白酶体亚基 LMP7 起主要作用。 此外，表现出isoLG加合物积累的SLE患者表现出独特的疾病特征。 具体目标是： (1) 确定 isoLG 加合物在 SLE 相关高血压和疾病中的作用 (2) 确定免疫蛋白酶体功能在isoLG加合抗原呈递中的作用 (3) 确定LMP7功能在免疫激活中的作用，isoLG加合抗原 为了实现这些目标，我们将招募 SLE 患者并获得 通过流式细胞术研究外周血单核细胞是否存在 isoLG 加合物。 将与抗原呈递细胞的独特群体内的IsoLG加合物水平进行比较。 临床参数以确定与加合物积累相关的参数来研究功能。 对于免疫蛋白酶体，我将利用缺乏免疫蛋白酶体三个全局亚基的小鼠 （TKO 小鼠）我还产生了免疫蛋白酶体胰凝乳蛋白酶亚基的条件敲除。 (LMP7fl/fl) 将与 CD11c-Cre 转基因动物杂交以产生抗原呈递细胞特异性 LMP7 缺陷动物将用于研究高血压和炎症的发展。 设置两种已建立的小鼠原发性高血压模型来研究 LMP7 的作用。 在 SLE 中，我建议检查 LMP7 抑制剂 PR-957 在 SLE B6.SLE123 小鼠模型中的作用。 此外，我将研究化学诱导的 SLE 模型中树突状细胞特异性 LMP7 缺失的影响 通过用降植烷处理 LMP7fl/fl/CD11c-Cre，将研究动物的高血压的发展， 免疫细胞扩增、自身抗体产生和肾损伤一起，这些研究有望实现。 此外，它们还将提供关于原发性高血压和 SLE 的新机制见解。 治疗这些病症的治疗机会。