巨噬细胞LncRNA AW112010在创伤后细菌感染耐受调控中的作用及分子机制

严重创伤后脓毒症发生率及病死率仍居高不下，探寻感染耐受分子有助于建立有别于抗生素、免疫调节剂之外的新型抗感染策略。巨噬细胞（Mø）中长链非编码RNA—AW112010及该序列中隐藏的开放阅读框（ORF）编码蛋白可上调宿主抗感染应答能力，但分子机制不清。本团队发现“Mø的AW112010在感染耐受诱导小鼠中持续高表达，但其在创伤、细菌感染驱动的瞬时高表达后降低至正常水平之下；上调该分子不影响Mø吞噬杀菌功能但可促进其向M2极化”，现提出“AW112010可正向调节创伤宿主对细菌感染耐受能力”的科学假设。本项目拟动态监测创伤后细菌感染小鼠Mø中AW112010、ORF编码蛋白水平；明确二者单独或联合参与创伤感染耐受调节的作用；阐明AW112010—转录因子—M2极化信号轴；尝试对Mø进行二者基因修饰并回输体内，以逆转创伤后细菌感染/脓毒症病理损害。该研究将为创伤感染的防治提供原创干预手段。

Morbidity and mortality of sepsis induced by severe trauma still remains high. Finding molecules modulating infection tolerance would be helpful to establish a novel strategy other than antibiotics or immunomodulators against infection. It has been reported that macrophages (Mø) long non-coding RNA AW112010 and the protein coded by open reading frame (ORF) hidden within its RNA sequence could up-regulate host response against infection, but the underlying molecular mechanism is unclear yet. Our research team previously found that the expression of AW112010 in Mø was persistently increased in mice induced by infection tolerance, its expression was decreased under the reference level after transient high expression following trauma or bacterial infection, and it could promote Mø polarization to M2 with unaltered Mø phagocytic activity and bactericidal function. Based on these findings we propose the scientific hypothesis that AW112010 may positively regulate the ability of trauma host in tolerance against bacterial infection. In this study we aim to dynamically determine the levels of AW112010 and protein coded by ORF after trauma followed by bacterial infection, make clear the role played by these two molecules in modulating tolerance against post-traumatic bacterial infection in a respective or co-action manner, clarify AW112010—transcription factors—M2 polarization signal axis, try to reverse pathological damage induced by post-traumatic bacterial infection or sepsis through transfusing Mø with genetic modification of these two molecules. This research will provide the original intervention approaches for the prevention and treatment of traumatic infection.