维生素D缺乏诱导NLRP3炎性小体活化在不明原因性复发性流产中的作用机制研究

不明原因性复发性流产(URSA)是育龄妇女常见病，约50%以上URSA维生素D3 (VD) 缺乏。文献和我们证实VD缺乏诱导Th1/Th17细胞偏倚导致URSA发生。已知NLRP3活化与URSA发生相关，且我们前期研究发现URSA在VDR低状态下蜕膜中NLRP3活化尤为显著，外周血中IL-1β和IL-18升高与VD水平呈负相关。故提出假设“VD缺乏诱导NLRP3炎性小体活化导致URSA发生”。本项目拟（1）利用临床样本确证VD缺乏诱导URSA患者NLRP3活化；（2）在不同VD条件下，体外共培养URSA的巨噬细胞和T细胞，探究VD缺乏导致NLRP3炎性小体活化的分子机制及其信号通路；（3）利用基因修饰动物模型在体研究NLRP3炎性小体在VD缺乏诱导流产中的作用及机制。揭示VD缺乏所致URSA发生的细胞和分子机制，为VD临床应用提供理论依据，揭示NLRP3可作URSA治疗新靶点及新策略。

Unexplained recurrent spontaneous abortion (URSA) is a common disease in women with childbearing age. More than 50% women with URSA lack vitamin D3 (VD) . The other articles and our previous studies found that VD deficiency induced Th1/Th17 polarization bias in women with URSA. As we knows, the activation of NLRP3 inflammasome is correlated with URSA; our previous studies found that the NLRP3 inflammasome of decidual macrophages in women with URSA was significantly increased and especially when VDR was lower; IL-1β and IL-18 in the peripheral blood of URSA are significantly increased and negatively correlated with the level of VD. Therefore, we hypothesized that "VD deficiency induced NLRP3 inflammasome activation and which led to URSA". In this project, we intend to (1) using clinical samples of women with URSA to further determine the activation of NLRP3 inflammasome in peripheral blood and decidua by VD deficiency; (2) co-culture macrophages and T cells of URSA and control groups under different VD conditions to explore the molecular mechanism and signal pathway of NLRP3 inflammasome activited by VD deficiency; (3) using gene modified animal model to study the role of NLRP3 inflammasome in VD deficiency induced abortion and elucidate its mechanism. In order to reveal the cellular and molecular mechanism of URSA caused by VD deficiency, provide theoretical basis for clinical application of VD, and reveal that inflammasome may be the new therapeutic target and strategy of URSA.