HMGN2调控雌激素介导的膀胱粘膜屏障结构与功能改变

We first reported that nuclear factor HMGN2 possessed anti-microbial and anti-viral effects. More recently, we also found that there were significant changes on estrogen signaling cascade, mucosal epithelial barrier related genes in HMGN2 knockdown cells, such as cell junction proteins and antimicrobial peptides. And these changes conform to biological logical theory; HMGN2 also changes urothelial cytoskeletal actin polymerization, reduces bacterial adhesion and invasion of cells. In accordance with other research progress in the relationship with HMG molecular and estrogen signaling cascade, and its impact on the mucosal barrier defense capability analysis.We propose HMGN2 may be involved in regulating the structure and function of estrogen-mediated changes in bladder mucosal barrier. Therefore we expect to demonstrate HMGN2 may affect the bladder mucosal antimicrobial peptides, inflammatory chemokines and cell differentiation or cell junction molecules through estrogen signaling cascade, which is important to regulate the structure and function of bladder mucosa mechanical and immunological barrier to reduce bacterial adhesion and invasion . The results will help to reveal the important role of HMGN2 in regulating the structure and function of bladder mucosal barrier, which is also significant to understanding the mechanisms of mucosal barrier defense.

我们首先报道了核因子HMGN2具有抗菌、抗病毒新功能，新近我们发现干扰HMGN2基因后，在转录水平上雌激素信号级联、粘膜上皮屏障结构或效应基因如细胞连接蛋白、抗菌肽等基因出现明显改变，且上述改变之间存在符合生物学理论的逻辑联系；HMGN2还可改变膀胱上皮细胞骨架微丝聚合，减少细菌粘附侵袭细胞。结合国内外HMG分子与雌激素信号级联间的关系及其对粘膜屏障防御能力影响研究进展分析，我们提出HMGN2可能参与调控雌激素介导的膀胱粘膜屏障结构功能改变的假设。为此我们将从粘膜机械、免疫屏障两个角度，在细胞、动物和临床三个层面，验证HMGN2是否通过雌激素信号级联，影响膀胱粘膜抗菌肽、炎症趋化因子及与细胞分化、细胞间连接相关效应分子产生，最终调节膀胱粘膜机械和免疫屏障结构与功能，减少细菌粘附侵袭。其结果将有助于揭示HMGN2在膀胱粘膜屏障结构与功能调节中所起的重要作用，也有助于深入理解粘膜屏障防御机制。

【项目背景】因HMGN2介导的膀胱粘膜屏障结构与功能改变机制尚不完全明确，对此，我们在细胞及整体水平开展了研究。.【研究内容】主要针对致病菌的粘附、内化过程所引起的天然免疫应答影响胞内菌的存活状态，我们探讨了HMGN2在其中扮演的角色，并对屏障结构改变进行了初步的探索。.【重要结果与关键数据】我们证实HMGN2可通过影响整合素α5β1受体信号，细胞骨架重排；且HMGN2基因作为microRNA (miR-155和miR-23a）靶标，调控了整合素α5β1的表达致使细菌粘附内化减少。发现HMGN2除可通过MAPK外，还可通过调控氧化应激经典通路Nrf2途径，影响了细胞骨架蛋白聚合和细菌的内化。并且HMGN2介导的AMPK信号通路，与致病菌操控的mTOR 信号通路相互作用，通过自噬行为改变，共同影响了对致病菌的清除或逃逸。在此基础上，我们发现HMGN2过表达通过下调紧密连接分子表达破坏了上皮细胞屏障功能，进而促进了膀胱上皮屏障对大肠杆菌的通透。课题组在对巨噬细胞脓肿分枝杆菌和耻垢分枝杆菌的清除机制研究中，我们证实HMGN2可以引起巨噬细胞由M0型向M1性转变，调控了促炎症因子与抑炎因子平衡。.以上实验表明：HMGN2在宿主细胞与致病菌相互作用过程中，从起始的细菌粘附阶段到结局的存活清除阶段，HMGN2均不是旁观者，而是免疫屏障重要的参与者。. 课题组在此期间培养研究生17人，发表文章12篇，参加学术会议4次，大会发言3次。同时，在此项目的资助下，3位年轻老师成功申请到自然科学青年基金。