小分子化合物调控Th17/Treg分化治疗银屑病的作用机制

调控Th17/Treg平衡在银屑病等IL-17为主要致病因子的疾病治疗中具有重要意义。Naïve T细胞向不同亚群分化具有不同代谢需求，因此通过调控代谢途径调节T细胞分化的作用机制亟待研究。申请人前期研究发现银屑病表皮细胞异常增殖的表观调控机制（JI，2015），近期阐明小分子化合物靶向单碳循环关键酶调节细胞增殖从而抑制小鼠类银屑病（EBioMedicine，2019）。通过类似化学蛋白质组学方法，申请人发现小分子衍生物靶向过氧化物酶体脂肪酸氧化关键酶，抑制naïve T向Th17细胞分化，同时促进向Treg细胞分化。鉴于此，推测过氧化物酶体脂肪酸氧化在调控Th17/Treg平衡中起重要作用。本项目将应用小分子-蛋白共结晶、X射线晶体衍射、代谢组学和条件性敲除小鼠等技术，解析关键酶介导的过氧化物酶体脂肪酸氧化在T细胞命运决定中的作用机制，探索干预Th17/Treg分化治疗银屑病的策略。

Regulating the balance between Th17 and iTreg cells is important for diseases in which IL-17 plays a pathogenic role. To develop from naïve T cells into distinct T cell lineages, activated T cells undergo a massive metabolic switch to cope with the demands of cell growth and division. However, how the metabolic pathways regulate T cells polarization remains largely unknown. Our previous studies reveal the epigenetic regulation mechanism of epidermal hyperplasia in psoriasis (The Journal of Immunology, 2015), and a natural small molecular compound AKBA which is the most bioactive ingredient of boswellic acids targets the key enzyme of one-carbon metabolism to regulate the proliferation of keratinocytes and suppress mouse model of psoriasis (BioMedicine, 2019). With the similar chemoproteomics method, we further identify the derivative of AKBA targets the major enzyme of peroxisomal fatty acid β-oxidation. The AKBA derivative could reprogram the differentiation of Th17 cells towards induced regulatory T cells under Th17-polarizing condition. Therefore, we hypothesize that peroxisomal fatty acid β-oxidation plays an important role in regulating Th17/Treg balance. In the proposed project, we will identify the interaction mechanism of AKBA derivative and the target protein, and investigate the function and mechanism of T cell peroxisome fatty acid oxidation in the regulation of T cell fate by using small molecular compound-target protein co-crystallization, X-ray crystallography, metabolomics, transgenic mouse and conditional knockout mouse. We will also explore the potential application in psoriasis treatment by targeting Th17/Treg differentiation.