ActA基因突变吕斯特菌促进骨髓造血干细胞增殖的分子机制研究

The radiation therapy is widely used in the clinical treatment among a variety of diseases, and the chance of exposure of the body radiation may be increased. Bone marrow hematopoietic suppression is the most common complication of radiotherapy. However, there are still no specific treatment. Our previous study found that ActA-Lm could promote bone marrow hematopoietic stem cells (HSC) proliferation and reduce the mortality rate through the activation and regulation of type I interferon reaction in radiated mice. Using a couple of gene knockout mice,including TLR2-/-, Myd88-/-, NOD2-/-, RIP2-/- and IFNAR-/-, We establish a mouse model of total body irradiation to investigate: (1)the expression of inflammatory mediators spectrum and motible changes of bone marrow HSC proliferation in mice after the treatment of ActA-Lm,(2)the role and regulatory mechanisms of type I interferon in the proliferation of bone marrow HSC promoted by Acta-Lm,(3)the key pattern recognition receptors and downstream signaling pathways activated by ActA-Lm. Our research will illustrate the key molecular mechanisms of Acta-Lm-promoted HSC proliferation, and open up a new strategy for hematopoietic protection.

放射性疗法在临床广泛应用于多种疾病的治疗，同时也增加了机体放射性暴露的机会。骨髓造血抑制是放疗最常见的并发症，而临床并无特效治疗手段。我们前期研究发现：Acta基因突变的吕斯特菌（ActA-Lm）可以通过激活和调控机体I型干扰素反应，促进放射小鼠的骨髓造血干细胞（HSC）增殖，降低小鼠的死亡率。本课题通过建立全身照射的小鼠模型，利用多种基因敲除小鼠（TLR2-/-, Myd88-/-，NOD2-/-，RIP2-/-以及IFNAR-/-），研究：(1) ActA-Lm作用后，放射小鼠体内炎症介质表达谱和骨髓HSC增殖变化；(2)I型干扰素在ActA-Lm促进骨髓HSC增殖中的作用和相关调控机制；(3)ActA-Lm激活I型干扰素反应的关键模式识别受体和下游信号通路。我们的研究将阐明Acta-Lm促进骨髓造血的重要分子机制，为造血保护领域开辟新策略，提供新手段。

放射性疗法在临床广泛应用于多种疾病的治疗，同时也增加了机体放射性暴露的机会。骨髓造血抑制是放疗最常见的并发症。本研究发现：ActA基因突变的吕斯特菌（ActA-Lm）可以通过激活机体I型干扰素反应，上调胆固醇25-羟化酶（CH25H）的表达，增加25羟基胆固醇（25HC）的合成。25HC促进放射照射小鼠的骨髓造血增生，提高小鼠生存率。我们的研究初步阐明ActA-Lm促进骨髓造血的重要分子机制。进一步对25HC 分子进行改构，有望增进其放疗保护功能。