辐射诱导表达上调的miR-5094通过下调STAT5b影响T细胞增殖

Inhibition of immune system is a common consequence of the exposure to radiation and the elucidation of its underlying mechanisms is expected to inspire the development of efficient countermeasures to protect astronauts on outer-space exploration missions, tumor patients taking radiotherapy, occupational radiation workers and even ordinary people. STAT5b is an important downstream target protein of interleukin-2 and involved in many biological processes including immune response by promoting T cell proliferation and differentiation. However, its regulation by microRNAs (miRNA) in cellular response to radiation remains unknown. . In our previous study, we identified a new human miRNA, miR-5094, which is up-regulated by X-ray irradiation, and verified that it directly binds to the 3'-untranslated region of STAT5b mRNA and consequently suppresses the protein expression of STAT5b. So, we take for granted that the miR-5094-STAT5b pathway is involved in the radiation response of T cells.. In this project, we are going to verify this hypothesis with experiments at cellular, molecular, and animal levels by detecting of the proliferation and apoptosis of T cells, and the expression and activation of STAT5b and its downstream proteins in case of the transfection of miR-5094 mimics, inhibitor or their strict control into T cells exposed to X-rays or carbon ion beams. The findings are expected to reveal the biological function of miR-5094-STAT5b pathway in T cell response to radiation and provide a promising means to protect immune system from ionizing radiation.

阐明辐射导致机体免疫抑制的机理、研发有效的防护措施对于执行深空探索任务的航天员、接受放疗的肿瘤患者和放射从业人员都至关重要。STAT5b是白介素2的重要下游蛋白，调控T细胞的增殖和分化，与机体免疫应答关系密切。我们的前期研究发现，电离辐照诱导miR-5094的上调，后者靶向调节STAT5b的表达。然而，STAT5b是否参与T细胞的辐照应激过程以及microRNA对STAT5b的调控机制都未见报道。本项目中，我们将借助细胞学和分子生物学手段，从分子、细胞、动物不同层次，研究常规辐射和重离子束对T细胞增殖、凋亡的影响，从多个角度考察miR-5094-STAT5b通路在T细胞辐射响应过程中的作用。本项目的开展将有助于完善STAT5b信号调控网络，揭示辐射导致机体免疫抑制的可能机制，为辐射防护措施的研发提供理论依据。

STAT5b 作为重要的细胞信号转导调控因子和 IL-2 信号通路的重要靶蛋白，鲜有见到其受到 miRNA 调节的相关报道。本课题利用X-rays、碳重离子等不同电离辐射作为处理条件，在分子、细胞、实验动物等不同层次开展了miR-5094的功能探索，考察了miR-5094对细胞增殖、凋亡等辐射应激响应的影响，分析了miR-5094在细胞辐照后的信号调控过程中的作用。研究结果显示，miR-5094可通过靶向抑制STAT5b的表达，抑制细胞增殖、促进细胞凋亡，影响细胞尤其是T细胞的辐射应激，从而参与机体的辐射免疫应答。本课题首次证实了miR-5094对STAT5b的靶向调控，为 STAT5b 信号网络增添了新的调控因子。其次，课题深化了我们对 STAT5b在辐照应激响应尤其是T细胞辐射应激过程中作用的了解，阐明了新的分子辐射生物学机制。