Metabolic Control of Systemic Autoimmunity

全身自身免疫的代谢控制

基本信息

批准号：
10361550
负责人：
Andras Perl
金额：
$ 48.6万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361550
关键词：
Adaptive Immune System Address Affect Aldehyde Reductase Anabolism Antibody Formation Antiphospholipid Antibodies Antiphospholipid Syndrome Arylesterase Autoantibodies Autoimmune Diseases Autoimmunity Biological Response Modifiers Blood Circulation CD3 Antigens CD8B1 gene Carbon Cells Chronic Citric Acid Cycle Complex DNA Development Electron Transport Enzymes Etiology Exhibits FRAP1 gene Female of child bearing age Fumarates Genetic Glomerulonephritis Glucose Glycolysis Goals Hepatocyte Human Immune response Immune system Inflammation Inflammatory Interleukin-17 Interleukin-4 Knowledge Liver Liver diseases Longitudinal Studies Lupus Lymphocyte Mediating Medical Metabolic Metabolic Control Metabolic Pathway Metabolism Mitochondria Modeling Mus NADH dehydrogenase (ubiquinone)NADP Nephritis Oxidation-Reduction Oxidative Stress Pathogenesis Pathway interactions Patients Pentosephosphate Pathway Pharmacology Plasma Population Production Proteins Public Health Regulation Regulatory T-Lymphocyte Research Resolution Role Sirolimus Stable Isotope Labeling Systemic Lupus Erythematosus T memory cell T-Cell Development T-Lymphocyte Testing Therapeutic Therapeutic Intervention Transaldolase Work aryldialkylphosphatase autoimmunity checkpoint base cell type chronic autoimmune disease comorbidity congenic constriction effective therapy gene therapy glycosylation in vivo innovation inorganic phosphate lupus prone mice metabolome mortality novel therapeutics overexpression reactive oxygen intermediate sensor side effect stable isotope stem systemic autoimmunity

项目摘要

ABSTRACT Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. The pathogenesis is partly attributed to compartmentalized oxidative stress inside and outside the immune system. The proposed studies will focus on a critical gap in knowledge - how metabolic pathways that neutralize oxidative stress control autoimmunity in SLE. The central hypothesis for this project is based on comprehensive metabolome studies that have showed a dominant impact of SLE on the pentose phosphate pathway (PPP) in lymphocytes of patients and T cells of lupus-prone mice undergoing lineage polarization; the results of which mimic the deficiency of transaldolase (TAL), a rate-limiting enzyme of the PPP. Lupus-prone mice exhibit activation of the mechanistic target of rapamycin (mTOR) and mitochondrial oxidative stress in the liver and antiphospholipid antibody (aPL) production prior to the onset of nephritis. Similar to lupus-prone strains, mice lacking TAL exhibit mTOR activation and overexpression of NDUFS3, a subunit of complex I in the mitochondrial electron transport chain (ETC) that triggers the production of reactive oxygen intermediates (ROI) and aPL, both of which respond to rapamycin treatment. TAL deficiency blocks the glycosylation and secretion of PON1 by the liver. This is attributed to carbon trapping in the PPP and depletion of UDP-GlcNAc which are also detectable in SLE patients and mice. Although PON1 loss in the plasma has been connected to aPL production and demonstrated in SLE, antiphospholipid syndrome (APS), and liver diseases, the underlying mechanisms remain unknown. Therefore, the Specific Aims will test our working hypothesis that TAL inactivation i) elicits cell type-specific carbon sequestration in the PPP and limits substrates for NADPH and GSH production and metabolism through the ETC and thus triggers a compensatory accumulation of oxidative stress-generating mitochondria, mTOR pathway activation and pro-inflammatory lineage skewing in the immune system; and ii) limits the availability of UDP-GlcNAc for glycosylation and secretion of PON1 by the liver, which in turn trigger aPL production in SLE and TAL deficiency. Under Aim 1, we will test the hypothesis that TAL-regulated carbon flux through the PPP causes cell-type specific accumulation of sedoheptulose 7-phosphate, depletion of NADPH and GSH, and redox-mediated mTOR activation to promote the expansion Th17, Tfh, and DN T cells and constriction of CD8 EMT cells and Tregs in SLE patients. Under Aim 2, we will delineate T-cell intrinsic metabolic checkpoints that control systemic autoimmunity in lupus-prone mice. Under Aim 3, we will determine the role of hepatocyte- derived oxidative stress in aPL production, pro-inflammatory lineage skewing in the immune system and lupus pathogenesis. The proposed research is significant because it will establish new, compartmentally defined metabolic checkpoints of autoimmunity with broad translational relevance for the pathogenesis and treatment of SLE. The approach is innovative as it will employ genetic checkpoints of oxidative stress and high-resolution stable isotope tracing of metabolic pathways to delineate lupus pathogenesis.

抽象的系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病。发病机制是部分归因于免疫系统内外的氧化应激。拟议的研究将集中在知识上的一个关键差距——如何控制中和氧化应激的代谢途径 SLE 中的自身免疫。该项目的中心假设基于全面的代谢组研究研究表明，SLE 对淋巴细胞中的戊糖磷酸途径 (PPP) 具有显着影响患者和狼疮易感小鼠的 T 细胞经历谱系极化；其结果模仿转醛醇酶 (TAL) 缺乏，转醛醇酶是 PPP 的限速酶。狼疮易感小鼠表现出雷帕霉素（mTOR）的机制靶点和肝脏中的线粒体氧化应激和抗磷脂肾炎发病前产生抗体（aPL）。与易患狼疮的品系类似，缺乏 TAL 的小鼠表现出 mTOR 激活和 NDUFS3（线粒体电子传递中复合物 I 的亚基）的过度表达链（ETC）触发活性氧中间体（ROI）和aPL的产生，两者都会做出反应予雷帕霉素治疗。 TAL 缺乏会阻碍肝脏糖基化和 PON1 的分泌。这是归因于 PPP 中的碳捕获和 UDP-GlcNAc 的消耗，这在 SLE 患者中也可检测到和老鼠。尽管等离子体中的 PON1 损失已与 aPL 生产相关并在 SLE 中得到证实，抗磷脂综合征（APS）和肝脏疾病的潜在机制仍不清楚。所以，具体目标将检验我们的工作假设，即 TAL 失活 i) 会引发细胞类型特异性碳 PPP 中的封存并通过以下方式限制 NADPH 和 GSH 生产和代谢的底物 ETC，从而触发产生氧化应激的线粒体 mTOR 的补偿性积累免疫系统中的通路激活和促炎谱系倾斜； ii) 限制可用性 UDP-GlcNAc 用于肝脏糖基化和分泌 PON1，进而触发 SLE 中 aPL 的产生和 TAL 缺乏症。在目标 1 下，我们将检验 TAL 通过 PPP 调节碳通量的假设导致景天庚酮糖 7-磷酸的细胞类型特异性积累、NADPH 和 GSH 的消耗，以及氧化还原介导的 mTOR 激活促进 Th17、Tfh 和 DN T 细胞的扩增以及 CD8 的收缩 SLE 患者的 EMT 细胞和 Tregs。在目标 2 下，我们将描述 T 细胞内在代谢检查点控制狼疮易感小鼠的系统性自身免疫。在目标 3 下，我们将确定肝细胞的作用 aPL 产生中的衍生氧化应激、免疫系统中的促炎谱系倾斜和狼疮发病。拟议的研究意义重大，因为它将建立新的、分区定义的自身免疫的代谢检查点与发病机制和治疗具有广泛的转化相关性系统性红斑狼疮。该方法具有创新性，因为它将采用氧化应激的基因检查点和高分辨率代谢途径的稳定同位素示踪可描绘狼疮发病机制。