炎症反应检查点分子SPINK7抑制嗜酸性粒细胞浸润缓解放射性结直肠纤维化的作用与机制研究

放射性肠纤维化（RIIF）是盆腹腔肿瘤放疗常见的并发症之一，严重影响患者生活质量，临床上缺乏有效防治措施。虽然其发病机制尚不清楚，但辐射损伤后嗜酸性粒细胞（Eos）的浸润激活被认为是肠组织纤维化发生发展的关键事件。课题组前期发现，炎症反应检查点分子SPINK7在RIIF中表达升高，SPINK7基因敲除小鼠呈现以Eos浸润显著增加为特征的纤维化加重表型。遂提出SPINK7通过抑制Eos浸润进而缓解RIIF的学术观点，但其机制有待厘清。本项目拟以SPINK7敲除鼠、骨髓移植嵌合鼠、Eos耗竭等在体模型系统阐明SPINK7通过抑制Eos浸润缓解RIIF的作用，进而以原代Eos、肌成纤维细胞等离体细胞模型评价SPINK7经CCL11/CCR3轴对Eos迁移、活化等功能的影响。本研究有望丰富对于RIIF的发生机制的理论认识，为RIIF的防治提供新的视点和依据。

Radiation-induced intestinal fibrosis (RIIF) is one of the common complications of pelvic and peritoneal tumor radiotherapy, which seriously affects the quality life of tumor patients. The infiltration and activation of eosinophils (Eos) after radiation injury is the key point in the occurrence and development of intestinal fibrosis, although its pathogenesis is still unclear. Previously, we found that SPINK7, an inhibitory checkpoint for inflammatory responses,is induced with significantly high expression levels in RIIF, and SPINK7 gene knockout mice showed an aggravating fibrosis phenotype characterized by Eos infiltration significantly increased. Therefore, SPINK7 is proposed to ameliorate RIIF by inhibiting Eos infiltration, but its mechanism needs to be clarified. In this project, in vivo models of SPINK7 knockout mice, bone marrow transplantation chimeric mice and Eos depletion mice will be used to systematically uncovered the role of SPINK7 in ameliorating RIIF by suppressing Eos infiltration, and then in vitro cell models such as primary Eos and myofibroblasts will be used to evaluate the role of SPINK7 in migration and activation of Eos through CCL11 / CCR3 axis. In summary, results of this project will both enrich the theoretical understanding of the occurrence mechanism of RIIF and provide a new perspective and basis for the prevention and treatment of RIIF.