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.

抽象的全身性红斑狼疮（SLE）是一种未知病因的自身免疫性疾病。发病机理是部分归因于免疫系统内部和外部的分室化氧化应激。提议研究将集中于知识的临界差距 - 如何中和氧化应激控制的代谢途径 SLE中的自身免疫性。该项目的中心假设基于全面的代谢组研究在淋巴细胞中，SLE对戊糖磷酸途径（PPP）的主要影响经受谱系极化的狼疮小鼠的患者和T细胞；哪个模仿的结果跨化酶（TAL）的缺乏，PPP的限速酶。容易发生的小鼠表现出激活的激活雷帕霉素（MTOR）和线粒体氧化应激的机械靶标在肝脏和抗磷脂中肾炎发作之前的抗体（APL）产生。与狼疮易发的菌株类似，缺乏TAL展览的小鼠 NDUFS3的mTOR激活和过表达，即线粒体电子传输中复合物I的亚基触发活性氧中间体（ROI）和APL的产生的链（ETC）雷帕霉素治疗。 TAL缺乏阻断肝脏对PON1的糖基化和分泌。这是归因于PPP中的碳捕获和UDP-GLCNAC的耗竭，这在SLE患者中也可检测到和老鼠。尽管血浆中的PON1损失已连接到APL生产并在SLE中证明，但抗磷脂综合征（AP）和肝病，潜在机制仍然未知。所以，具体目的将检验我们的工作假设，即失活i）引起细胞类型特异性碳 PPP中的隔离，并限制了NADPH和GSH生产和代谢的底物等等，从而触发氧化应激产生线粒体的补偿性积累免疫系统中的途径激活和促炎谱系偏斜； ii）限制了可用性 UDP-GLCNAC用于肝脏对PON1的糖基化和分泌，这反过来触发SLE中的APL产生和TAL缺乏症。在AIM 1下，我们将检验以下假设：TAL调节的碳通量通过PPP 引起sed肽7-磷酸盐的细胞类型特异性积累，NADPH和GSH的耗竭，以及氧化还原介导的MTOR激活以促进膨胀Th17，TFH和DN T细胞以及CD8的收缩 SLE患者的EMT细胞和Treg。在AIM 2下，我们将描述T细胞内在的代谢检查点控制容易发生的小鼠的全身自身免疫。在AIM 3下，我们将确定肝细胞的作用 APL产生中的氧化应激，免疫系统中的促炎谱系和狼疮发病。拟议的研究很重要，因为它将建立新的，分隔的定义自身免疫的代谢检查点与发病机理和治疗具有广泛的转化相关性 sle。该方法具有创新性，因为它将采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追踪描绘狼疮发病机理。