TEA结构域转录因子1a促进斑马鱼中性粒细胞发育的生物学作用及机制研究

中性粒细胞缺陷相关疾病临床危害大、治疗效果不佳。研究中性粒细胞发育及机制，从源头上改善中性粒细胞缺陷，具有重大临床意义。斑马鱼具有与人类高度相似的基因组、造血发育过程，是研究造血发育重要的动物模型。申请人前期创新性发现TEAD1a可从髓系最早期开始促进斑马鱼中性粒细胞发育，通过CRISPR/Cas9诱导tead1a基因突变可导致斑马鱼中性粒细胞缺陷表型，而过表达TEAD1a及下游分子通路可挽救缺陷表型，深入研究发现这种表型很可能是通过下游gata1/notch通路介导。据此，本项目拟进一步深入研究，阐明TEAD1a在斑马鱼中首先通过抑制gata1转录促进髓系前体细胞（CMP）向粒系-单核系原始细胞（GMP）分化，之后通过上调notch信号通路进一步促进中性粒细胞分化发育的机制。本项目将为阐释中性粒细胞发育提供新的理论依据，为中性粒细胞缺陷的治疗提供新策略。

The diseases related to neutrophil deficiency can do great harm to patients and present poor response to treatment. It is of great importance to study the mechanism of neutrophil development and fundamentally cure its defect. Zebrafish has a high similarity of genome and hematopoietic development process with human, and therefore an ideal model for hematopoietic development study. Previously, the applicant found that TEAD1a can promote neutrophil development in zebrafish from the earliest stage of myelopoiesis. Mutation of tead1a induced by CRISPR/Cas9 led to defective neutrophil development in zebrafish, and overexpression of TEAD1a or its downstream molecular pathways rescued the defective phenotype. Furthermore, we found that this phenotype was probably mediated by downstream gata1/notch pathway. Based on this, this project intends to verify that TEAD1a firstly promotes the differentiation from CMP to GMP by inhibiting the transcription of gata1, and then promotes neutrophil differentiation and development by promoting the notch signaling pathway. This project will provide a new theoretical basis for the interpretation of neutrophil development and a new strategy for the treatment of neutrophil deficiency.