J亚群禽白血病病毒（ALV-J）感染主要引起鸡的造血细胞恶性增生与免疫抑制，然其致病致瘤机制尚不清楚。我们前期发现，ALV-J及其囊膜蛋白Env可下调SHP-2磷酸化水平；高表达SHP-2可促进ALV-J复制，而敲除SHP-2则抑制ALV-J复制。作为原癌基因PTPN11编码的酪氨酸磷酸酶，SHP-2的表达及其活性改变已被证明与造血细胞的恶性增生、儿童白血病及多种人的恶性肿瘤疾病有关。那么SHP-2与ALV-J及其Env的互作是否与ALV-J的致病致瘤有关？互作分子基础又是什么？本项目拟通过定点突变、免疫沉淀、质谱分析、CRISPR-Cas9基因编辑等技术，对SHP-2在ALV-J致病致瘤中作用及其分子机制进行研究。本项目顺利开展将揭示ALV-J及其Env与SHP-2的互作分子基础，ALV-J致病致瘤新机制，为开发抗ALV-J或其它反转录病毒策略提供新靶点与理论依据。

Avian leukosis virus subgroup J (ALV-J) mainly causes hematopoietic malignancy and immune suppression. However, little is known about the molecular mechanism for ALV-J pathogenesis and oncogenesis. Our recent studies found that ALV-J and its envelope protein (Env) could down-regulate the phosphorylated SHP-2, the over-expression of SHP-2 could promote the replication of ALV-J and the knockout of SHP-2 could efficiently inhibit the replication of ALV-J. As a tyrosine phosphatase encoded by the proto-oncogene PTPN11, the expression of SHP-2 and its altered activity have been demonstrated to be closely related with the hematopoietic malignancy, juvenile myelomonocytic leukaemia and lots of human cancer diseases. Therefore, does the interaction between SHP-2 with ALV-J or Env contribute to the pathogenesis and oncogenesis of ALV-J ? What is the molecular basis for that interaction ? In this study, we plan to study on the role and molecular mechanism of SHP-2 in ALV-J pathogenesis and oncogenesis through techniques such as site mutagenesis, co-immunoprecipitation, mass-spectrum and CRISPR-Cas9. The results from this project will reveal the molecular basis for the interaction between ALV-J or Env with SHP-2, discover new insights for ALV-J pathogenesis and oncogenesis, and provide novel targets and pave the way for developing better strategies against ALV-J or other retroviruses.