E3泛素连接酶TRIM33通过调控Th17细胞分化及IL-17表达介导重症哮喘发病的机制研究

Th17/IL-17在重症哮喘的发病中具有关键作用，但调控Th17/IL-17的分子机制尚需进一步阐明。最新研究显示CD4+T细胞中的E3泛素连接酶TRIM33可促进Th17细胞的分化及IL-17的表达，但其是否在哮喘的发病中扮演关键角色目前国内外尚未有研究涉及。本课题前期研究显示TRIM33在重症哮喘小鼠肺组织中的表达显著升高，因此提出TRIM33有可能通过促进Th17细胞分化及IL-17表达上调，从而可能在促进重症哮喘发病中发挥关键作用。本课题拟采用CD4+T细胞TRIM33特异性基因敲除的小鼠构建重症哮喘小鼠模型并评估其气道炎症及气道高反应性，以明确TRIM33在重症哮喘发病中的关键作用，并通过体内外研究结合探讨TRIM33调控重症哮喘的分子机制。此外，还研究气道内滴注TRIM33shRNA对重症哮喘小鼠的治疗作用，为TRIM33作为新的重症哮喘治疗候选靶标提供初步理论依据。

Th17/IL-17 plays an important role in the pathogenesis of severe asthma. But the underlying mechanisms how Th17/IL-17 mediate the asthma remain further clarification. Recent researches showed that TRIM33, with an E3 ubiquitin ligase domain, could promote the differentiation of Th17 cells and the expression of IL-17, but whether it plays a key role in the pathogenesis of asthma has not been studied. Our preliminary studies demonstrated that the expression of TRIM33 was significantly increased in the severe asthma mice, suggesting that TRIM33 may play its role in severe asthma by promoting Th17 cell differentiation and upregulating the expression of IL-17. We plan to use CD4+ T cells-specific TRIM33 knockout mice to construct severe asthma model, and evaluate the airway inflammation and airway hyperresponsiveness in mice, so as to clarify the key role of TRIM33 in the pathogenesis of severe asthma and to explore the mechanism of TRIM33 in regulating severe asthma. Furthermore, we will examine the therapeutic effect of TRIM33 shRNA intratracheal transduction on severe asthma mice to provide a preliminary theoretical basis for TRIM33 as a novel potential target in severe asthma treatment.