神经母细胞瘤（NB）的分子靶向治疗是研究热点。预实验发现IL-4及其受体IL-4Rα在人NB组织和细胞高表达；IL-4Rα敲减、敲除或IL-4中和抗体抑制人NB细胞增殖、迁移和浸润；Gαi1/3是IL-4信号通路的新关键蛋白。IL-4处理诱导IL-4Rα-Gαi1/3耦联。而Gαi1/3敲除、敲减则抑制IL-4信号转导和NB细胞增殖、迁移。我们提出Gαi1/3耦联IL-4Rα介导IL-4信号转导促NB细胞生长。本课题将运用shRNA、CRISPR/Cas9、敲除细胞株、基因突变、过表达等方法结合裸鼠荷瘤及原位癌模型，深入研究IL-4-IL-4Rα促NB细胞生长作用；重点解析Gαi1/3介导IL-4信号转导促NB细胞生长作用分子机制；检测IL-4-IL-4Rα-Gαi1/3通路在人NB组织中表达，明确其和NB临床指标相关性。旨在为NB诊断和治疗突破提供新的靶点（IL-4Rα-Gαi1/3）。

Molecularly-targeted therapy is the current research focus for neuroblastoma (NB). Our preliminary results show that IL-4 its receptor IL-4Rα are overexpressed in human NB tissues and NB cells. Conversely, IL-4Rα knockdown, knockout or adding the IL-4 neutralizing antibody significantly inhibited NB cell proliferation, migration and invasion. Gαi1/3 (G protein inhibitory α subunits 1 and 3) could be the novel and key signaling proteins for the IL-4 cascade. Following IL-4 treatment, IL-4Rα associated with Gαi1/3. Reversely, Gαi1/3 knockdown or knockout significantly inhibited IL-4-induced signal transduction, NB cell proliferation and migration. We propose that Gαi1/3 associate with IL-4Rα to mediate IL-4 signal transduction, thus promoting NB cell growth. In the current proposal, the strategies including shRNA, CRISPR/Cas9, knockout cell lines, gene mutation and overexpression as well as nude mice models will be utilized. We will study the role of IL-4-IL-4Rα on NB cell growth, in vitro and in vivo. The role and underlying mechanism of Gαi1/3 in mediating IL-4 signal transduction and NB cell growth will be studied in detail. The expression of IL-4-IL-4Rα-Gαi1/3 cascade components in human NB tissues will be tested, and their correlations with the clinical features of NB patients will be analyzed. The aim of this study is to identify possible novel targets for the early diagnosis and treatment of NB (IL-4Rα-Gαi1/3).