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（由申请人提供）：系统性红斑狼疮 (SLE) 的病因尚不清楚，但其发病机制至少部分归因于 T 细胞功能障碍，初步研究揭示了雷帕霉素复合物 1 的机制靶点的激活。 mTORC1）存在于狼疮 T 细胞中，在疾病爆发之前，导致 SLE 患者中 mTORC1 的上游，减少的耗竭。谷胱甘肽 (GSH)、活性氧中间体 (ROI) 的增强和线粒体自噬缺陷的双盲安慰剂对照临床试验的结果表明，N-乙酰半胱氨酸 (NAC) 阻断可逆转 GSH 消耗。因此，拟议的研究将通过确定控制氧化应激和正常 T 细胞发育的代谢途径如何促进狼疮发病机制来解决关键的知识空白。中心假设是，GSH 耗竭主要通过促炎性 T 细胞的 mTORC1 依赖性扩增来驱动 SLE 的发病机制。该研究的基本原理是，在阐明了基因控制的代谢之后。 促进 GSH 消耗和 mTORC1 激活从而引发狼疮发病机制的途径，可以使用新的和潜在协同的方法来预防和治疗 SLE。在令人信服的初步数据的指导下，我们的假设将在三个具体目标中进行测试：1) 描述 SLE 的发病机制。导致狼疮 T 细胞中产生氧化应激的线粒体积累的代谢程序 2) 确定 GSH 消耗在 mTORC1 依赖性 T 细胞谱系中的作用；规范 SLE 患者的纵向研究；3) 确定 GSH 消耗在狼疮易感小鼠的全身性自身免疫发病机制中的作用，目标 1：电子传递链复合物 I 和狼疮中 ND3 亚基的 S-亚硝基化。 ND2 和 ATP6 中的线粒体 DNA (mtDNA) 多态性将被评估为目标 2、GSH 消耗和 ROI 产量增加的原因。 mTORC1 激活将在体外进行基因靶向，以逆转促炎性 T 细胞发育，重点是 CREM-a/IL-4 介导的 CD8 T 细胞向 DN T 细胞的转分化以及 HIF1a/IL-17 介导的 Tregs 耗竭在目标 3 下，GSH 消耗将通过转醛醇酶失活进行建模，并作为狼疮易发小鼠的疾病发病机制进行评估。意义重大，因为它将增进我们对正常和自身免疫条件下 T 细胞谱系发育的理解，并与确定 SLE 的新治疗靶点相关。该方法是创新的，因为它利用代谢途径基因来调节 T 细胞，从而摆脱了现状。这些结果将为我们了解控制氧化应激的代谢途径及其在疾病发病机制中的作用开辟新的视野，同时为 SLE 的治疗提供新的机制目标。