Metabolic Control of T-cell Lineage Specification in SLE

SLE 中 T 细胞谱系规范的代谢控制

• 批准号: 9000610
• 负责人: Andras Perl
• 金额: $ 40.4万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000610
• 关键词: Acetylcysteine; Address; Adverse effects; Affect; Amino Acids; Antioxidants; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; CD8B1 gene; Cell Lineage; Cells; Cellular biology; Cessation of life; Complex; Controlled Clinical Trials; Cytokine Activation; DNA; Data; Development; Disease; Double-Blind Method; Drug usage; Electron Transport; Etiology; FRAP1 gene; Female of child bearing age; Flare; Functional disorder; Gene Expression Profile; Genes; Genetic Polymorphism; Goals; HIF1A gene; Health; Immune System and Related Disorders; Immune system; In Vitro; Inbred MRL lpr Mice; Inflammation; Inflammatory; Interleukin-17; Interleukin-4; Knowledge; Link; Longitudinal Studies; Lupus; Lupus Nephritis; Mediating; Medical; Membrane Potentials; Metabolic; Metabolic Control; Metabolic Pathway; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Molecular; Mus; NADH dehydrogenase (ubiquinone); Nuclear; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Patients; Placebo Control; Population; Prevention; Production; Proteins; Public Health; Reduced Glutathione; Research; Role; SOD2 gene; Sirolimus; Source; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; Tacrolimus Binding Protein 1A; Testing; Therapeutic; Tissues; Transaldolase; VDAC1 gene; Work; base; chronic autoimmune disease; congenic; cytokine; effective therapy; improved; in vivo; innovation; lupus prone mice; mortality; programs; protein complex; reactive oxygen intermediate; receptor; sensor; signal processing

 DESCRIPTION (provided by applicant): The causes of systemic lupus erythematosus (SLE) are unknown, however, the pathogenesis is attributed, at least in part, to T-cell dysfunction. Preliminary studies reveal activation of the mechanistic target of rapamycin complex 1 (mTORC1) in lupus T cells which precedes disease flares and causes pro-inflammatory lineage specification in SLE patients. Upstream of mTORC1, depletion of reduced glutathione (GSH), enhanced production of reactive oxygen intermediates (ROI), and defective mitophagy are newly identified. Outcomes of a double-blind placebo-controlled clinical trial show that therapeutic reversal of GSH depletion by N-acetylcysteine (NAC) blocks mTORC1 in vivo. Therefore, the proposed studies will address a critical knowledge gap by determining how metabolic pathways that control oxidative stress and normal T-cell development contribute to lupus pathogenesis. The central hypothesis is that primarily GSH depletion drives the pathogenesis of SLE through mTORC1-dependent expansion of pro-inflammatory T cells. The rationale for the proposed research is that, after elucidating the genetically controlled metabolic pathways that promote GSH depletion and mTORC1 activation and thus trigger lupus pathogenesis, new and potentially synergistic approaches can be used for prevention and treatment of SLE. Guided by compelling preliminary data, our hypothesis will be tested in three Specific Aims: 1) to delineate the metabolic program that causes the accumulation of oxidative stress-generating mitochondria in lupus T cells; 2) to identify the role of GSH depletion in mTORC1-dependent T-cell lineage specification in longitudinal studies of SLE patients; and 3) to determine the role of GSH depletion in the pathogenesis of systemic autoimmunity in lupus-prone mice. Under Aim 1, S-nitrosylation of ND3 subunit in complex I of the electron transport chain and lupus-linked mitochondrial DNA (mtDNA) polymorphisms in ND2 and ATP6 will be assessed as causes of increased ROI production. Under Aim 2, GSH depletion and mTORC1 activation will be genetically targeted in vitro for reversing pro-inflammatory T-cell development focusing on CREM-a/IL-4-mediated trans-differentiation of CD8 T cells to DN T cells and HIF1a/IL-17-mediated depletion of Tregs in SLE patients. Under Aim 3, GSH depletion will be modeled by the inactivation of transaldolase and evaluated as a cause of disease pathogenesis in lupus-prone mice. The proposed research is significant because it will advance our understanding of T-cell lineage development in normal and autoimmune conditions with relevance for identifying new treatment targets in SLE. The approach is innovative as it departs from the status quo by utilizing metabolic pathway genes to regulate T-cell development. The results will open new horizons in our understanding of the metabolic pathways that control oxidative stress and its role in disease pathogenesis while providing new mechanistic targets for treatment of SLE.

 描述（由适用提供）：全身性红斑狼疮（SLE）的原因尚不清楚，但是，至少部分归因于T细胞功能障碍。初步研究揭示了雷帕霉素复合物1（MTORC1）在狼疮T细胞中的机械靶标的激活，该狼疮T细胞先于疾病叶片，并导致SLE患者的促炎血统规范。新鉴定出MTORC1上游，减少谷胱甘肽（GSH）的耗竭（GSH），增强活性氧中间体（ROI）的产生以及有缺陷的线粒体。双盲安慰剂对照临床试验的结果表明，N-乙酰半胱氨酸（NAC）对GSH部署的治疗逆转（NAC）阻止了MTORC1体内的MTORC1。因此，拟议的研究将通过确定控制氧化物应激和正常T细胞发育有助于狼疮发病机理的代谢途径如何来解决关键知识差距。中心假设是，原发性GSH耗竭通过促炎性T细胞的MTORC1依赖性扩张驱动SLE的发病机理。拟议研究的理由是，阐明了遗传控制的代谢后 促进GSH部署和MTORC1激活的途径，从而触发狼疮的发病机理，新的和潜在的协同方法可用于预防和治疗SLE。在引人注目的初步数据的指导下，我们的假设将以三个特定的目的进行检验：1）描绘代谢程序，该程序导致狼疮T细胞中氧化胁迫产生的线粒体的积累； 2）确定在SLE患者的纵向研究中，GSH部署在MTORC1依赖性T细胞谱系中的作用； 3）确定GSH部署在容易发生的小鼠中系统性自身免疫发病机理中的作用。在AIM 1下，在ND2和ATP6中，电子传输链和狼疮连接的线粒体DNA（mtDNA）多态性的ND3亚基的S-亚硝基化将作为ROI产生增加的原因评估。在AIM 2下，将以基因靶向GSH部署和MTORC1激活，用于逆转促炎性T细胞发育，重点是CREM-A/IL-4介导的CD8 T细胞对DN T细胞和HIF1A/IL-17介导的TREG在SELE患者中的Tregs部署的treg。在AIM 3下，GSH部署将通过跨层溶解酶的灭活并被评估为狼疮易发的小鼠的疾病发病机理的原因。拟议的研究很重要，因为它将在正常和自身免疫性条件下提高我们对T细胞谱系发展的理解，并与确定SLE中的新治疗靶标有关。这种方法具有创新性，因为它通过利用代谢途径基因来调节T细胞发育，从而脱离了现状。结果将在我们对控制氧化物胁迫及其在疾病发病机理中的作用的同时提供新的机械靶标的代谢途径的理解开辟新的视野。