Metabolism, infection and immunity in inborn errors of metabolism

先天性代谢缺陷中的代谢、感染和免疫

• 批准号: 10025122
• 负责人: Peter McGuire
• 金额: $ 165.06万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10025122
• 关键词: Address; Affect; Animal Model; Apoptosis; Attention; Biological Models; Bypass; Cell physiology; Cells; Clinical Data; Clinical Protocols; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Depressed mood; Disease; Functional disorder; Genets; Goals; Human; Immune; Immune Targeting; Immune system; Immunity; Inborn Errors of Metabolism; Infection; Innate Immune System; International; Kupffer Cells; Liver; Liver diseases; Mediating; Memory B-Lymphocyte; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Mus; Organ; Paper; Patients; Pediatric cohort; Phenotype; Play; Publications; Publishing; Role; Seminal; Study models; T memory cell; T-Cell Activation; T-Lymphocyte; Techniques; Therapeutic; Time; Vaccines; Work; alternative oxidase; base; complex IV; cytochrome c oxidase; data modeling; data reduction; fatty acid oxidation; immune activation; immune function; long chain fatty acid; macrophage; metabolomics; mitochondrial metabolism; mouse model; patient oriented; pediatric patients; programs; response; translational research program

The overall goal of our translational research program is to understand the interplay between activation of the immune system and mitochondrial metabolism (i.e. immunometabolism) using mitochondrial disease as a model system. Our clinical protocol serves as the basis for our transnational studies. Recently, we described vulnerability to vaccine preventable diseases in a cohort of pediatric patients with mitochondrial disease. To explore the mechanisms involved in depressed memory B-cell function, we have created a mouse model of cytochrome c oxidase (COX, complex IV in OXPHOS) deficiency. Preliminary data suggests that COX deficiency results in perturbations in long lived memory B-cells. Recognizing an immune phenotype involving T-cell memory responses in our patients with mitochondrial disease, we constructed a model of T-cell COX deficiency by targeting COX10, an assembly factor for COX (Cell Metab, 2017). Using this model, we demonstrated the unique role of COX as a metabolic checkpoint in T-cell activation by mediating apoptosis. Following up on this publication, we created a mouse model of SURF1 deficiency using CRISPR. SURF1 is another COX assembly factor that produces severe mitochondrial disease in humans. To our surprise, despite having low COX activity, this mouse model displays normal T-cell function, unlike COX10 deficient mice. Both models will allow us to dissect COX functional domains and their role in T-cell function. Furthermore, we will also explore therapies aimed at bypassing COX deficiency in COX10 mice by expressing an alternative oxidase (AOX) in T-cells. Continuing on this theme of the role of mitochondrial metabolism in T-cells, we have been involved in an international collaborative project addressing a fundamental question regarding the role of mitochondrial fatty acid oxidation in T-cells. The accepted dogma is that mitochondrial fatty acid oxidation promotes memory T-cell formation. Using patient clinical data and mouse models of fatty acid oxidation, we aided in demonstrating that mitochondrial fatty acid oxidation was dispensable for determining T-cell memory phenotypes. As s result, we contributed to a seminal publication (Cell Metab, 2018) and high profile review (Immunol Rev 2018) challenging this dogma. Both of the aforementioned accomplishments highlight the central role clinical research plays in our program. Based on our patient-centered approach to addressing fundamental questions in immunometabolism, we published a review extolling the virtues of studying mitochondrial disease as a model system for answering critical questions regarding the role of the mitochondria in immune cell function (Metabolism 2018). In addition to work in T-cell immunometabolism, we have also continued to explore the role of the immune system in modulating end organ metabolism. Using a metabolomics approach with complex data reduction techniques, we characterized the pathophysiology of metabolic perturbations that occur as a result of infection in a mouse model of mitochondrial long chain fatty acid oxidation (Mol Genet Metab, 2018). This paper and a review on the role of the immune system in promoting metabolic dysregulation in the liver during infection (Mol Genet Metab, 2017) highlights the role of the innate immune system and resident macrophages (e.g. Kupffer cells) in modulating end organ metabolism (J Mol Med, 2019). This work continues in a mouse model of mitochondrial hepatopathy where targeting the immune system is being explored as a therapeutic avenue.

我们的转化研究计划的总体目标是了解免疫系统激活与线粒体代谢（即免疫代谢）的相互作用，使用线粒体疾病作为模型系统。 我们的临床方案是我们跨国研究的基础。最近，我们描述了在一组线粒体疾病的儿科患者中易受疫苗可预防疾病的脆弱性。为了探索抑郁记忆B细胞功能中涉及的机制，我们创建了一种细胞色素C氧化酶（COX，OXPHOS中的复合物IV）的小鼠模型。初步数据表明，COX缺乏会导致长期存在的记忆B细胞的扰动。 认识到线粒体疾病患者中涉及T细胞记忆反应的免疫表型，我们通过靶向Cox10（Cox的组装因子）构建了T细胞COX缺乏症的模型（Cell Metab，2017）。使用此模型，我们通过介导凋亡来证明Cox作为T细胞激活中代谢检查点的独特作用。跟进本出版物，我们使用CRISPR创建了Surf1缺乏症的鼠标模型。 Surf1是另一个Cox装配因子，可在人类中产生严重的线粒体疾病。令我们惊讶的是，尽管COX活性较低，但该鼠标模型显示出正常的T细胞功能，与COX10缺乏小鼠不同。两种模型都将使我们能够剖析COX功能域及其在T细胞函数中的作用。此外，我们还将通过在T细胞中表达替代氧化酶（AOX）来探索旨在绕过Cox10小鼠中COX缺乏症的疗法。 继续以线粒体代谢在T细胞中作用的作用的主题，我们参与了一个国际协作项目，该项目解决了关于线粒体脂肪酸氧化在T细胞中的作用的基本问题。公认的教条是线粒体脂肪酸氧化促进记忆T细胞的形成。使用患者的临床数据和脂肪酸氧化的小鼠模型，我们帮助证明了线粒体脂肪酸氧化是可用于确定T细胞记忆表型的。结果，我们为开创性出版物（Cell Metab，2018）和知名度评论（Immunol Rev 2018）做出了贡献，挑战了这一教条。 上述两项成就都凸显了临床研究在我们的计划中的核心作用。基于我们以患者为中心的方法来解决免疫代谢中的基本问题，我们发表了一篇评论，介绍了研究线粒体疾病作为一种模型系统的优点，用于回答有关线粒体在免疫细胞功能中作用的关键问题（代谢性2018年）。 除了从事T细胞免疫代谢的工作外，我们还继续探索免疫系统在调节终端器官代谢中的作用。 使用代谢组学方法和复杂的数据还原技术，我们表征了代谢扰动的病理生理学，这些病理学是由于感染而导致的线粒体长链脂肪酸氧化的小鼠模型（Molenet Metab，2018）。本文以及对免疫系统在感染过程中促进肝脏代谢失调作用的综述（Mol Genet Metab，2017年）凸显了先天免疫系统和常驻巨噬细胞（例如Kupffer细胞）在调节终端器官代谢中的作用（J Mol Med，2019年）。这项工作仍在线粒体肝病的小鼠模型中继续进行，其中针对免疫系统作为治疗大道探索。