miR-23b/24-1簇防治烧伤后脓毒症所致MODS的系统研究

脓毒症所致MODS是危重烧伤病人的首位致死原因。缩短烧伤脓毒症易感期的同时降低其易感性是危重烧伤救治成功的关键环节。我们前期发现“正向调控Smad3信号可降低机体对烧伤脓毒症的易感性，但因抑制创面上皮化而延长易感期”，这成为限制Smad3靶策略转化应用的瓶颈。根据最新研究发现“Smad家族蛋白差异表达谱具有组织细胞特异性”和“miRNA簇具有多靶点精准调控功能”，我们设想：靶向Smad家族蛋白的miRNA簇调控策略可能实现“既上调体内重要脏器单核-巨噬细胞Smad3信号进而降低脓毒症易感性，又下调皮肤表皮细胞Smad3信号、缩短脓毒症易感期”的双赢效果。为验证这一假设，我们选用前期高通量测序和生物信息学分析筛选得的miR-23b/24-1簇，拟采用CRISPR/Cas9、簇成员共表达等实验技术，从分子、细胞和动物模型多层面系统验证上述假说，以期为临床危重烧伤救治提供新思路和手段。

Multiple Organ Dysfunction Syndrome(MODS) secondary to burn-induced sepsis is the leading cause of death in severely burned patients. Shortening the susceptible period to burn-induced sepsis and reducing its susceptibility are two key principles in successful treatment of those patients. Our previous study found that "enhancement of Smad3 signaling can reduce the susceptibility to burn-induced sepsis, but prolong the susceptible period by delaying wound healing", which was a bottleneck limiting the application of Smad3-targeted therapy. According to the latest research finding that " expression of Smad proteins is tissue/cell-specific" and "miRNA clusters can regulate signal transduction precisely based on its potential multiple targets in one signal pathway", we hypothesize that miRNA cluster targeting Smad family may achieve a win-win effect, not only enhancing Smad3 signaling in the mononuclear-macrophage thus reducing the susceptibility to burn-induced sepsis, but also weakening Smad3 signaling in skin epidermal cells thus shortening the susceptible period for burn-induced sepsis. Focusing on miR-23b/24-1 cluster revealed by high-throughput sequencing and bioinformatics analysis in our preliminary research, we plan to conduct a systematic study involving molecular, cellular, and animal experiments using CRISPR/Cas9, cluster member co-expression and other techniques, to validate our hypothesis, in order to provide new ideas and means for clinical treatment of burn-induced sepsis and MODS.