Metabolism, infection and immunity in inborn errors of mitochondrial metabolism

线粒体代谢先天性缺陷的代谢、感染和免疫

基本信息

项目摘要

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). Recently, we published a mouse model of mitochondrial hepatopathy where targeting the immune system was being explored as a therapeutic avenue (Jestin et al., Mol Metab, 2020).
我们的转化研究项目的总体目标是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,使用线粒体疾病作为模型系统。

项目成果

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Peter McGuire其他文献

Peter McGuire的其他文献

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{{ truncateString('Peter McGuire', 18)}}的其他基金

Basic and clinical studies in immune function and metabolism
免疫功能和代谢的基础和临床研究
  • 批准号:
    8565575
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
Basic and clinical studies in immune function and metabolism
免疫功能和代谢的基础和临床研究
  • 批准号:
    8750713
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
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:
    8948396
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
Metabolism, infection and immunity in inborn errors of mitochondrial metabolism
线粒体代谢先天性缺陷的代谢、感染和免疫
  • 批准号:
    10920205
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
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:
    9152751
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:
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:
    9570584
  • 财政年份:
  • 资助金额:
    $ 169.36万
  • 项目类别:

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