斑马鱼runx1突变所致常见变异型免疫缺陷病（CVID）模型的建立

Pathogenesis of common variable immunodeficiency disease (CVID) is not clear. There are no specific drugs for CVID. It’s known that runx1 regulates the hematopoiesis and abnormal expression of runx1 causes multiple blood diseases. But it has not been reported that runx1 mutation is associated with CVID. Zebrafish is an ideal animal model for study on lymphocytic development and drug screening..Previously, we have got a runx1 mutant line with a point mutation which results in premature translation termination. We found following phenotypes from a small number of runx1 mutant line survived to adult based on explicit phenotypes of embryonic hematopoietic defects: (1)There are decreased myeloid cells and accumulated lymphocytes in peripheral blood and kidney of adult runx1 mutant line; (2)The percentage of B lymphocytes is significant higher and the percentage of T lymphocytes is significant lower in adult runx1 mutant line than WT；(3)The adult runx1 mutant line has developmental and functional deficiency of B lymphocytes. We proposed the hypothesis that runx1 mutant line may be an animal CVID model..In this proposed research, we aim (1) to identify the hematopoietic and immune phenotypes of runx1 mutant line precisely; and (2) to clarify the cellular and molecular mechanism that how runx1 mutation results in CVID; and (3) to establish an ideal zebrafish CVID model and investigate its pathogenesis, typology, clinic data comparison and to provide new theory, new path and new drug target for the risk warning, molecular diagnosis, treatment strategies and high throughput drug screening of CVID.

常见变异型免疫缺陷病（CVID）发病机制不清，缺乏特异药物。已知runx1调节造血发育，其异常表达可引起多种血液系统疾病，但未见报道与CVID关联。斑马鱼是研究淋巴细胞发育和活体高通量药物筛选理想的模式动物。 .我们前期获得一个runx1点突变导致翻译提前终止的突变体，在明确其胚胎期造血缺陷表型的基础上，发现少数可存活的成鱼具有以下初步表型：①肾脏血、外周血中髓系细胞减少，淋巴细胞增多；②B淋巴细胞数量减少，T淋巴细胞增多；③B淋巴细胞发育缺陷，功能缺陷。我们假设斑马鱼runx1突变体有可能是一种CVID动物模型。.本项目拟进行：①突变体造血与免疫表型的精确鉴定；②阐明runx1突变导致CVID的细胞与分子机制；③斑马鱼CVID模型的建立及其发病机制、分型和临床对比, 以期为CVID的风险预警、分子诊断、治疗策略和高通量药物筛选提供新理论、新途径和新靶标。

在“常见变异型免疫缺陷病(common variable immunodeficiency, CVID)”的发病机制研究中取得重要进展。斑马鱼与人类B细胞发育具有共同的分子基础，斑马鱼runx1突变会产生类似于人类CVID的表型，表现为B细胞的数量、成熟及免疫功能受限，而T细胞发育则不受影响。B细胞的产生和功能失调常常导致多种人类疾病，包括白血病、CVID和X-连锁的无球蛋白血症。CVID是一种临床异质性的原发性免疫缺陷性疾病(PID)，其主要特点是易受感染和免疫应答不足，IgG、IgA和/或IgM抗体产生明显减少，淋巴细胞发育不良，尤其是B细胞发育不良是CVID的主要病理生理原因。CVID发病过程中淋巴细胞发育及其相关机制尚不明确，目前仅有针对表型特征的对症处理，如输入免疫球蛋白以缓解免疫力降低、防止反复感染等发病状况。该研究利用斑马鱼runx1突变体建立了CVID模型，探讨了RUNX 1对B细胞生长的调控作用以及疾病的发生机制。该模型首次利用可遗传的runx1突变体在斑马鱼中建立了一个强有力的CVID模型，为进一步探讨CVID患者的B细胞发育和潜在的治疗提供了机会。【Open Biology. 2018 Jul;8(7). pii: 180043.】

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