Targeting Pathogenic Endothelial Dysfunction in Lupus Nephritis

针对狼疮性肾炎的致病性内皮功能障碍

• 批准号: 10487863
• 负责人: JAMES C OATES
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487863
• 关键词: Address; Adhesions; Affect; Anti-Inflammatory Agents; Antigen-Antibody Complex; Arteries; Atherosclerosis; Biological Markers; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Chemotaxis; Cholesterol; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Couples; Coupling; Diabetes Mellitus; Disease; Disease remission; Dose; Effector Cell; Endothelial Cells; Endothelium; Event; FDA approved; FOXO1A gene; Fibrosis; Flare; Functional disorder; Funding; Future; Gene Expression; General Population; Genes; Goals; Health; Heart Diseases; Histologic; Human; Hypertension; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Infiltrate; Innate Immune Response; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Lead; Lupus; Lupus Nephritis; Mediating; Medicine; Methods; Modeling; Mus; Mycophenolate; Myocardial Infarction; NOS3 gene; Necrosis; Nephritis; Nitric Oxide; Onset of illness; Outcome; Oxidation-Reduction; Oxidative Stress; PDGFRB gene; Pathogenicity; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Platelet-Derived Growth Factor Receptor; Prevalence; Prevention; Production; Publishing; Reactive Oxygen Species; Remission Induction; Rodent; Serum; Signal Transduction; Spleen; Stimulus; Superoxides; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Translating; Vascular Diseases; Veterans; Withdrawal; Work; base; cytokine; effective therapy; effectiveness testing; endothelial dysfunction; experience; glomerular endothelium; hypertensive; immunoregulation; improved; improved outcome; in vivo; lupus-like; macrophage; macrovascular disease; monocyte; monomer; pharmacodynamic biomarker; podocyte; predicting response; prevent; primary endpoint; response biomarker; sepiapterin; single cell analysis; single-cell RNA sequencing; standard care; targeted treatment; tetrahydrobiopterin; therapeutic target; therapy development; transcriptome sequencing; translation to humans; treatment response

Systemic lupus erythematosus (SLE) is an immune complex-mediated disease in which clinical disease manifests after an innate immune response. Endothelial cells (EC) are conditional effector cells activated by inflammatory stimuli to produce intracellular reactive oxygen species (ROS) and signal for influx of inflammatory cells into tissue. We have published that endothelial nitric oxide synthase (eNOS) modulates inflammation in lupus nephritis (LN) and that uncoupling of EC eNOS (which reduces production of anti-inflammatory nitric oxide (NO) and increases production of pro-inflammatory ROS) is a potential therapeutic target in SLE. We hypothesize that sepiapterin, a compound that couples eNOS, will improve LN outcomes and vascular function in murine LN and work by modulating the PI3Kinase/Akt pathway to reduce expression of inflammation and fibrosis genes in mice and in cultured glomerular endothelial cells. We further hypothesize that the proposed approach may have off target effects, particularly in T cells, monocyte/macrophages, and podocytes. To address this overarching hypothesis, the following specific aims are proposed: Specific Aim 1) Determine the effect of sepiapterin in murine LN on clinical and histologic LN outcomes, large vessel endothelial function, and pharmacodynamic markers of treatment response. We hypothesize that sepiapterin will improve LN outcomes and vascular function in murine LN. To determine the effect of and optimal therapeutic indication for ECD targeted therapy, we will use the NZM2410 model of spontaneous LN and compare groups with and without sepiapterin treatment to determine effect on three different endpoints. 1) preventing/prolonging LN onset with sepiapterin monotherapy, 2) in mycophenolate-treated mice, improving/hastening induction of remission with sepiapterin as an adjunctive therapy, and 3) after inducing remission, prolonging/preventing LN flare with sepiapterin monotherapy after mycophenolate withdrawal. LN clinical and histologic parameters and large vessel endothelial function will be the primary endpoints. Biomarkers of systemic oxidative stress will serve as exploratory pharmacodynamic indicators. Specific Aim 2. Determine differential gene expression and phosphokinase signaling events, with a focus on the PI3K/Akt pathway, induced in human glomerular endothelial cells (HRGECs) by LN serum and modulated by sepiapterin. Based on our published and preliminary studies, we hypothesize that inflammatory gene expression and PDGF receptor/PI3K/Akt/FoxO1 signaling induced by LN flare serum can be modulated by sepiapterin in HRGECs. Knowledge of pathways activated by LN flare serum that both initiate redox-regulated pathways and that can be modulated by restoring coupling to eNOS will be important for rational development of therapies to target ECD in LN. We will culture HRGECs with serum from SLE patients with active nephritis or a cytokine mix and perturb signaling through the PDGFR, PI3K, and Akt to determine the effect on gene expression and NO and superoxide production. Specific Aim 3. Determine differential inflammatory and fibrosis gene expression and pathway enrichment in endothelial cells, infiltrating inflammatory cells, and podocytes from renal glomerular tissue and in T cells from the spleen in mice treated with increasing doses of sepiapterin. Based on our published and preliminary studies, we hypothesize that candidate PI3K-Akt signaling gene enrichment (both potentiated by and inducing of oxidative stress in a feed forward fashion) will be modulated by sepiapterin. NZM2410 mice will be treated with increasing doses of sepiapterin and renal cortical and spleen tissue analyzed by single cell RNA sequencing. The ultimate goal of our translational group is to target ECD to improve cardiovascular and renal outcomes in LN. Given the prevalence of cardiovascular disease in LN, we will study endothelium-dependent vascular function to inform early human studies of cardiovascular prevention. The aims proposed here will demonstrate the most effective treatment indications, pharmacodynamic markers of response, and alternate or adjunctive targets to reduce inflammatory ECD in LN and other diseases of endothelial dysfunction in Veterans.

系统性红斑狼疮（SLE）是一种免疫复合物介导的临床疾病