促发炎症反应是脂毒性发挥β细胞损害的重要途径，但分子机制未完全阐明，故无法靶向干预。已知游离脂肪酸（FFA）通过Toll 样受体4（TLR4）介导胰岛炎性损伤，但FFA并不直接绑定TLR4。我们前期研究发现胎球蛋白A（FetA）可激活β细胞的TLR4而协同脂毒性损害，推测FetA可能具有介导FFA与TLR4串话的作用。为此，我们拟体外采用基因干扰和过表达技术调控细胞基因表达，体内运用FetA、TLR4基因敲除小鼠模型等方法，分5个层次验证假设：首先观察FFA、FetA和TLR4与β细胞功能的关联；接着分析FetA是否参与脂毒性细胞损害；进而研究FFA激活TLR4是否需要FetA介导；并验证FFA，FetA，TLR4蛋白间的相互作用；最后探讨FFA-FetA-TLR4复合物发挥作用是否经由PKC-JNK-AP-1-PANDER-caspase-3通路。以期为干预β细胞脂毒性损害提供新的靶点。

Induction of proinflammatory responses in β cells is an important mediator of lipotoxicity, but this molecular mechanisms of lipotoxicity is not clear and thus can not target for therapeutic interventions. Previous studies have shown that free fatty acids (FFA) can activate pancreatic islet inflammation through Toll-like receptor 4 (TLR4). However, FFA does not bind directly to TLR4. We have found that Fetuin A（FetA）could increase the activity of TLR4 to promote FFA-induced lipoapoptosis in β cells, indicating that FetA may act as the medium that allows FFA-TLR4 crosstalk. So, this study is going to investigate the mediated effect of FetA by using the technology of RNAi and gene overexpression to regulate gene expression in vitro and FetA or TLR4 gene knockout mice models in vivo, as the following five experiments: at first, we will observe the association among FFA, FetA ,TLR4 and β-cell function;then, we want to analyze whether FetA participates in lipotoxicity damage of β-cell; third, we intend to investigate whether FFA-induced TLR4 signaling requires FetA; fourth, we will try to find the evidence of the interaction among FFA, FetA and TLR4; at last ,we will further investigate whether the effect of FFA-FetA-TLR4 complexes is conducted by PKC-JNK-AP-1-PANDER- caspase-3 pathway.In summary,this study is to search for the new target of lipotoxicity on β-cell.