Metabolic Control of Systemic Autoimmunity

全身自身免疫的代谢控制

• 批准号: 10132228
• 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
• 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/10132228
• 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

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.

摘要 系统性红斑狼疮(SLE)是一种病因不明的自身免疫性疾病。其发病机制是 部分归因于免疫系统内外的隔断性氧化应激。建议数 研究将集中在知识上的一个关键差距--如何中和氧化应激控制的代谢途径 系统性红斑狼疮的自身免疫性。该项目的中心假设是基于全面的代谢组研究。 已显示SLE对淋巴细胞中磷酸戊糖途径(PPP)的主要影响 患者和狼疮易感小鼠的T细胞经历谱系极化；其结果模拟 PPP的限速酶转醛醇酶(TAL)缺乏。狼疮易感小鼠表现出激活的 雷帕霉素的作用靶点与肝脏线粒体氧化应激和抗磷脂 在肾炎发病前产生抗体(APL)。类似于易患狼疮的菌株，缺乏TAL的小鼠表现出 线粒体电子传递中复合体I亚单位NDUFS3的mTOR激活和过度表达 触发产生活性氧中间体(ROI)和APL的链(ETC)，这两种物质都对 接受雷帕霉素治疗。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的耗尽，这在SLE患者中也可以检测到 还有老鼠。尽管血浆中PON1的丢失与APL的产生有关，并在SLE中表现出来， 抗磷脂综合征(APS)和肝脏疾病，其潜在机制仍不清楚。因此， 这些特定的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和LIMITS底物中的隔离作用通过 等，从而触发产生氧化应激的线粒体的补偿性积累，mTOR 免疫系统中的途径激活和促炎谱系倾斜；以及ii)限制了 UDP-GlcNAc用于肝脏糖基化和PON1的分泌，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通过购买力平价调节碳通量的假设 导致细胞类型的7-磷酸七碳硫糖的特异性积聚，NADPH和GSH的耗竭，以及 氧化还原介导的mTOR激活促进Th17、Tfh和DNT细胞的扩增和CD8的收缩 系统性红斑狼疮患者外胚层细胞和树突状细胞的研究在目标2下，我们将描绘T细胞内在代谢检查点 控制狼疮易感小鼠的系统自身免疫。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，免疫系统和狼疮中的促炎谱系倾斜 发病机制。拟议的研究具有重要意义，因为它将建立新的、划分定义的 自身免疫的代谢检查点与发病机制和治疗的广泛翻译相关性 系统性红斑狼疮。这种方法是创新的，因为它将使用氧化应激和高分辨率的遗传检查点 代谢途径的稳定同位素示踪描绘狼疮发病机制。