靶向阻断HIF-2纳米粒联合超声辐照调控NF-κB/iNOS信号通路治疗重症急性胰腺炎的作用机制研究

Severe acute pancreatitis (SAP) is a common severe acute disease in clinical practice, which is characterized by rapid course of disease, multiple complications and high mortality. HIF-2 is a newly discovered cytokine containing ODD domain and is the most important member of the inflammatory/hypoxic micro-environment. Our prior research has also discovered that HIF-2 plays an important role in the occurrence and development of SAP, but its mechanism remains to be further explored. With respect to the above, in this project, by integrating bio-nanotechnology and gene targeting technology, an albumin nano/SonoVue ultrasound micro-bubbles carrier system targeting HIF-2 gene was constructed to achieve high-efficiency and sustained release. Meanwhile, with targeted blockage of HIF-2 gene through ultrasound irradiation, the regulatory effect of HIF-2 gene on the proliferation and apoptosis of the intestinal mucosal epithelial cells in SAP was explored at multiple levels of molecular, cell and animal models. This study revealed that HIF-2 could activate the expression of NF-κB to up-regulate the expression of target genes such as miR-105 and Occludin in the downstream of NF-κB/iNOS signaling pathway. Accordingly, it clarified the mechanism of inflammatory/hypoxic micro-environment on intestinal epithelial cell injury of SAP. The present study will provide new strategy for target gene selection and gene carrier optimization in intestinal barrier injury of SAP.

重症急性胰腺炎（SAP）是临床常见的急危重症，其病程进展迅速、并发症多，死亡率高。HIF-2是新近发现的一个含有ODD结构域的细胞因子，是机体炎症/缺氧微环境中最重要的一员，我们的前期研究也发现：HIF-2在SAP的发生、发展中起重要作用，但其作用机制还有待进一步研究。基于此，本项目利用生物纳米技术与超声辐照技术相融合，构建靶向HIF-2基因的白蛋白纳米/SonoVue超声微泡载体系统实现高效、缓释，并联合超声辐照靶向阻断HIF-2基因，从分子、细胞、动物模型多水平探讨HIF-2基因对SAP肠上皮细胞增殖、凋亡的调控，揭示HIF-2通过激活NF-κB表达，从而上调NF-κB/iNOS信号通路下游靶基因miR-105、Occludin等表达的分子机制，明确炎症/缺氧微环境对SAP肠粘膜上皮细胞损伤的作用机理，本研究将为SAP肠屏障损伤中靶基因选择和基因载体的优化提供新的策略。

重症急性胰腺炎是一种始于局部而累及全身的危急重症，其病程进展迅速，并发症多，常伴多器官功能衰竭（MODS）。在美国，每年有27.5万急性胰腺炎患者住院，总医疗费用高达250亿美元，过去10年，住院人数增加了20%。肠道不仅是重症急性胰腺炎发生时损伤的重要器官，而且肠粘膜屏障损伤还可进一步加重 SAP。新近国外研究表明，多种细胞因子与 SAP 时肠道黏膜损伤严重程度显著相关，炎症介质可与晚期糖基化终末产物受体RAGE、Toll 样受体TLR2、TLR4、TLR9等胞膜受体结合，通过相关信号通路使激活的 NF-κB 进入细胞核，上调炎性因子的基因表达水平并使其大量释放，从而损伤肠黏膜屏障，导致 SAP 时的全身炎症反应、多器官功能障碍，因此在治疗原发病的同时对肠粘膜屏障的保护至关重要。.SAP 时肠道黏膜屏障损伤是一个复杂的过程，SAP 早期的肠黏膜损伤程度与临床病情严重程度及继发感染的发生相关，并且可能导致临床病情的恶化，因此，改善 SAP 患者肠黏膜损伤对于其控制病情至关重要，但目前许多参与其中的细胞、分子相互间的关系仍不明确。.本研究团队通过构建靶向HIF-2基因的白蛋白/SonoVue载体系统实现高效、缓释，并联合超声辐照靶向阻断HIF-2基因，从分子、细胞、动物模型多水平探讨HIF-2基因对SAP肠粘膜上皮细胞增殖、凋亡的调控，揭示HIF-2通过激活NF-κB表达，从而上调NF-κB/ iNOS信号通路下游靶基因miR-105、Occludin等表达的分子机制，明确炎症/缺氧微环境对SAP肠粘膜上皮细胞损伤的作用机理。本研究为重症胰腺炎致肠粘膜屏障损伤治疗中靶基因选择和基因载体的优化提供新的策略。