Iduna通过多聚ADP核糖基化调节创伤性脑损伤后的炎症反应研究

Traumatic brain injury(TBI) is an important unsolved problem in medicine, which has high incidence and morbidity. Effective clinical interventions for definitive therapy in traumatic brain injury is deficient at present. Inflammation is one of the most important pathogenesis in traumatic brain injury. Inflammation became a research hotpot in treating secondary injury of TBI, while the related molecular pathogenesis is not entirely clear. Poly(ADP-ribosylation) has a close relationship with inflammation. Related articles and proposer’s preliminary researches show poly(ADP-ribosylation) could regulates inflammatory response in traumatic brain injury by marking Iduna, but the downstream working mechanism is remained unclarified. We recently discovered: ①the levels of Iduna protein and mRNA had a significantly increase after TBI; ②Iduna could regulate Tankyrase/Axin/Wnt signaling pathway. These researches suggest Iduna regulates Tankyrase/Axin/Wnt signaling pathway after marked by poly(ADP-ribosylation). Established on the traumatic brain injury plat form, this project wished to furtherly clarify the dependency of Iduna on poly(ADP-ribosylation) , complete Iduna centered inflammation regulation network in TBI and provide experimental foundation and theoretical basis for TBI treatment in clinic.

创伤性脑损伤发生率高、死亡率高，缺乏特异性和针对性治疗干预手段，是亟待解决的医学难题。炎症反应是创伤性脑损伤重要的病理机制，是治疗创伤性脑损伤后继发性损伤的研究热点，但相关分子病理机制尚未完全明确。多聚ADP核糖基化与炎症反应密切相关，相关文献和申请人前期研究表明多聚ADP核糖基化可能通过标记Iduna蛋白，调节创伤性脑损伤后的炎症反应，但是其下游作用机制尚不明确。我们近期发现：①Iduna蛋白和mRNA水平在创伤性脑损伤后均会明显升高；②Iduna能够调节Tankyrase/Axin/Wnt信号通路。以上研究提示多聚ADP核糖基化标记的Iduna蛋白进一步调控Tankyrase/Axin/Wnt信号通路。本课题在创伤性脑损伤平台上，进一步明确Iduna对多聚ADP核糖基化的依赖程度，完善以Iduna为中心的创伤性脑损伤炎症反应调控网络，为治疗创伤性脑损伤提供实验基础和理论依据。

创伤性脑损伤发生率高、死亡率高，是一类重大公共卫生问题，但目前临床上对于创伤性脑损伤后继发性损伤的缺乏有效的针对性治疗干预手段。炎症反应是创伤性脑损伤后最重要的病理机制之一，由炎症入手治疗创伤性脑损伤是现在的研究热点，但相关分子病理机制尚未完全明确。多聚ADP核糖基化与炎症反应密切相关，相关文献和申请人前期研究表明Iduna蛋白可能通过多聚ADP核糖基化标记后，调节创伤性脑损伤后的炎症反应。本课题在已建立的离体/在体的创伤性脑损伤模型上，首次证实Iduna蛋白对在TBI后对大脑及神经元起保护作用，并能抑制TBI引起的炎症反应，而且该效应依赖于多聚核糖基化对Iduna蛋白的标记。同时研究还证实，iduna能够调节Tankyrase/Axin/Wnt信号通路，并通过该通路进一步影响TBI后炎症反应。为临床上从炎症入手治疗TBI、保护及修复神经功能提供重要的理论依据和新的治疗靶点。