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: 8902578
• 负责人: Andras Perl
• 金额: $ 40.25万
• 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/8902578
• 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; Female of child bearing age; Flare; Functional disorder; Gene Expression Profile; Genes; Genetic Polymorphism; Goals; HIF1A gene; 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; Relative (related person); 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; public health relevance; 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。初步研究揭示了狼疮T细胞中雷帕霉素复合物1（mTORC 1）的机制靶点的激活，其先于疾病发作并导致SLE患者的促炎谱系特化。mTORC 1的上游，还原型谷胱甘肽（GSH）的耗尽，活性氧中间体（ROI）的产生增加，和有缺陷的线粒体自噬是新发现的。一项双盲安慰剂对照临床试验的结果显示，通过N-乙酰半胱氨酸（NAC）治疗性逆转GSH耗竭可在体内阻断mTORC 1。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缺口。主要假设是GSH耗竭通过mTORC 1依赖性促炎T细胞扩增驱动SLE的发病机制。这项研究的基本原理是，在阐明了基因控制的代谢后， 通过阻断促进GSH耗竭和mTORC 1活化并因此触发狼疮发病机制的途径，新的和潜在的协同方法可用于预防和治疗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检验：1）描述导致狼疮T细胞中产生氧化应激的线粒体积累的代谢程序; 2）在SLE患者的纵向研究中确定GSH耗竭在mTORC 1依赖性T细胞谱系特化中的作用;以及3）确定GSH耗竭在狼疮易感小鼠的全身性自身免疫发病机制中的作用。根据目标1，将评估电子传递链复合物I中ND 3亚基的S-亚硝基化以及ND 2和ATP 6中狼疮相关线粒体DNA（mtDNA）多态性是否为ROI产生增加的原因。在目标2下，GSH消耗和mTORC 1活化将在体外被遗传靶向，用于逆转促炎性T细胞发育，重点是CREM-a/IL-4介导的CD 8 T细胞向DN T细胞的转分化和SLE患者中HIF 1a/IL-17介导的TcR消耗。根据目标3，GSH耗竭将通过转醛醇酶的失活来建模，并作为狼疮易感小鼠中疾病发病机制的原因进行评价。这项研究意义重大，因为它将促进我们对正常和自身免疫性疾病中T细胞谱系发育的理解，并与确定SLE新的治疗靶点有关。该方法是创新的，因为它通过利用代谢途径基因来调节T细胞发育而脱离了现状。这些结果将为我们理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靶点。