血清淀粉样蛋白A3(SAA3)在急性胰腺炎中的作用及机制研究

急性胰腺炎（AP）是由胰腺的自身消化损伤引发的炎症反应。目前对重症急性胰腺炎尚无有效药物，相关机制及新药靶标研究备受关注。血清淀粉样蛋白A（SAA）在AP病人血中高表达，但是否参与调控AP未知。我们前期发现雨蛙素诱导AP小鼠模型中胰腺组织SAA3水平显著上调，胰腺损伤及急性肺损伤在Saa3-/-小鼠中明显减弱。体外SAA3蛋白能直接调控腺泡细胞功能，但机制不明。本课题拟从SAA3的体内作用入手，利用Saa3-/-小鼠建立不同动物模型明确SAA3对AP的调控作用；从巨噬细胞及腺泡细胞功能角度研究SAA3在AP进程中的细胞调控机制；探明SAA3通过TLR2, FPR2受体调节腺泡细胞功能，促进其坏死和炎性反应的分子机制；并通过CRISPR-Cas9的gRNA文库筛选新的可能参与SAA3调控腺泡细胞功能的新靶标。最终揭示SAA3调控AP损伤的分子病理机制，为AP的治疗提供数个潜在新型药物靶标。

Acute pancreatitis (AP) is potentially lethal disease characterized by pancreatic tissue damage and inflammation, which is currently lack of effective treatments. Therefore, it is of importance to determine the molecular and pathological mechanisms of AP and identify new potential drug targets. Our previous studies have demonstrated that serum amyloid A protein 3 (SAA3) is significant elevated in mice pancreas with caerulein-induced AP. SAA3 deficiency significantly reduced caerulein-induced pancreatic damage and systematic inflammatory response, we also found that SAA3 can mediated the function of acinar cells in vitro. However, the molecular mechanism of SAA3 on regulating AP and acinar cell remains largely unknown. Therefore, we will comprehensively determine the role and mechanisms of SAA3 in AP by the following specific aims: (1) To determine the effect of SAA3 in caerulein or L-arginine-induced acute pancreatitis by using Saa3-/- mice and SAA3 recombinant protein; (2) To discover whether SAA3 regulates AP through modulating function of macrophage and acinar cells; (3) To determine how SAA3-TLR2 or SAA3-FPR2 signal modulates necrosis and cytokine production by acinar cells; (4) To screening for novel molecular that may involved in regulating SAA3 signal in acinar cells by CRISPR-Cas9 mediated gRNA library. Collectively, our studies will not only reveal the effect and molecular pathological mechanisms of SAA3 in regulating AP, but also provide several novel drug targets for therapeutic intervention of AP.