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.

我们的翻译研究计划的总体目标是以线粒体疾病为模型系统，了解免疫系统的激活和线粒体代谢(即免疫代谢)之间的相互作用。 我们的临床方案是我们跨国研究的基础。最近，我们描述了一组患有线粒体疾病的儿科患者对疫苗可预防疾病的易感性。为了探索记忆B细胞功能低下的机制，我们建立了细胞色素c氧化酶(COX，OXPHOS中的复合体IV)缺乏的小鼠模型。初步数据表明，COX缺乏会导致长寿记忆B细胞的紊乱。 认识到我们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COX的组装因子COX10(Cell Metab，2017)构建了T细胞COX缺陷的模型。利用这个模型，我们证明了COX作为代谢检查点在T细胞活化中的独特作用，它通过介导细胞凋亡。在这篇文章之后，我们使用CRISPR建立了SURF1缺乏症的小鼠模型。SURF1是另一种COX组装因子，可导致人类严重的线粒体疾病。令我们惊讶的是，尽管COX活性很低，但这个小鼠模型显示出正常的T细胞功能，不像COX10缺陷小鼠。这两个模型都将使我们能够剖析COX功能区及其在T细胞功能中的作用。此外，我们还将探索通过在T细胞中表达一种替代氧化酶(AOX)来绕过COX10小鼠COX缺陷的治疗方法。 继续线粒体新陈代谢在T细胞中的作用这一主题，我们参与了一个国际合作项目，解决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。利用患者的临床数据和小鼠的脂肪酸氧化模型，我们帮助证明了线粒体脂肪酸氧化对于确定T细胞的记忆表型是必不可少的。因此，S，我们为一本开创性的出版物(细胞代谢，2018年)和高调评论(免疫修订版2018)做出了贡献，挑战了这一教条。 上述两项成就都突出了临床研究在我们的计划中所发挥的核心作用。基于我们以患者为中心解决免疫代谢基本问题的方法，我们发表了一篇综述，称赞研究线粒体疾病作为回答有关线粒体在免疫细胞功能中的作用的关键问题的模式系统的优点(新陈代谢2018)。 除了T细胞免疫代谢方面的工作外，我们还继续探索免疫系统在调节末端器官代谢中的作用。使用具有复杂数据简化技术的代谢组学方法，我们表征了由于感染线粒体长链脂肪酸氧化小鼠模型而发生的代谢扰动的病理生理学(Mol Genet Metab，2018)。这篇论文和关于免疫系统在促进感染期间肝脏代谢失调中的作用的综述(Mol Genet Metab，2017)强调了先天性免疫系统和常驻巨噬细胞(例如Kupffer细胞)在调节末端器官代谢中的作用(J Mol Med，2019)。这项工作在线粒体肝病小鼠模型中继续进行，目前正在探索以免疫系统为靶点作为治疗途径。