Metabolic impact of a polymorphism in the mitochondrial gene mt-Cytb on the pathogenesis of psoriasis

线粒体基因 mt-Cytb 多态性对银屑病发病机制的代谢影响

• 批准号: 443999492
• 负责人: Professor Dr. Saleh M. Ibrahim
• 金额: --
• 依托单位: Klinik für Dermatologie, Allergologie und Venerologie (Hautklinik)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/443999492?language=en
• 关键词: Metabolic; impact; polymorphism; mitochondrial; gene

The etiology of psoriasis is complex, inferring multifactorial interactions between genetic traits and environmental factors, innate and adaptive immunity. Recent research efforts have uncovered extensive interaction between cellular metabolic pathways and inflammatory processes (immunometabolism) in chronic inflammatory diseases. Mitochondria play a critical role in the regulation of cellular metabolism as they are a central component of the cellular energy production and conversion between anabolic and catabolic processes. Mitochondria affect many cellular processes, and take part in the regulation of inflammatory processes by controlling cellular metabolism in immune cells; consequently, mitochondrial functions are relevant in the pathomechanisms of chronic inflammatory conditions. Mitochondria carry their own genome, mitochondrial DNA (mtDNA) encoding several subunits of the oxidative phosphorylation system, which constitutes a key component of the cellular energy production. Mutations in the mtDNA reportedly link to mitochondrial dysfunction, thus such mutations result in cellular dysfunctions. In fact, dysfunctions in mitochondrial complex III results in immune cell impairment in mice. In parallel, a recent study identified a variation in the mitochondrial complex III gene is associated with psoriasis patients. Thus, we hypothesized that mutations in mitochondrially encoded complex III gene is associated with pathology of psoriasis. In this research proposal, we will 1) evaluate the impact of the mtDNA variant in the mitochondrial complex III gene (mt-Cytb) in psoriasis disease models, using a conplastic mouse strain (C57BL/6J-mt129S1/SvlmJ) and wild-type strain (C57BL/6J), 2) investigate cellular and mitochondrial functions in disease responsible cell types (i.e., γδT cells and dendritic cells) isolated from C57BL/6J-mt129S1/SvlmJ and C57BL/6J mice, and 3) integrate cellular metabolomics and transcriptomics data of the aforementioned immune cells to identify the mt-Cytb gene variant-derived potential mediators that control the molecular pathways involved in psoriasis pathogenesis. The expected findings will provide a basis for a novel therapeutic strategy for psoriasis.

银屑病的病因是复杂的，推断遗传性状和环境因素，先天性和适应性免疫之间的多因素相互作用。最近的研究工作揭示了慢性炎症性疾病中细胞代谢途径和炎症过程（免疫代谢）之间的广泛相互作用。线粒体在细胞代谢的调节中起关键作用，因为它们是细胞能量产生和合成代谢与分解代谢过程之间的转换的中心组分。线粒体影响许多细胞过程，并通过控制免疫细胞中的细胞代谢来参与炎症过程的调节;因此，线粒体功能与慢性炎症病症的病理机制相关。线粒体携带自己的基因组，线粒体DNA（mtDNA）编码氧化磷酸化系统的几个亚基，其构成细胞能量产生的关键组分。据报道，mtDNA中的突变与线粒体功能障碍有关，因此这种突变导致细胞功能障碍。事实上，线粒体复合物III的功能障碍会导致小鼠免疫细胞受损。与此同时，最近的一项研究发现，线粒体复合物III基因的变异与银屑病患者有关。因此，我们假设，在神经编码的复合物III基因突变与银屑病的病理。在这项研究计划中，我们将1）使用共体型小鼠品系（C57 BL/6 J-mt 129 S1/SvlmJ）和野生型品系（C57 BL/6 J）评估线粒体复合物III基因（mt-Cytb）中mtDNA变体在银屑病疾病模型中的影响，2）研究疾病责任细胞类型（即，γδT细胞和树突状细胞），以及3）整合上述免疫细胞的细胞代谢组学和转录组学数据，以鉴定mt-Cytb基因变体衍生的潜在介质，其控制银屑病发病机制中涉及的分子途径。预期的发现将为银屑病的新治疗策略提供基础。