斑马鱼runx1突变所致常见变异型免疫缺陷病（CVID）模型的建立

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。

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.