动脉瘤是临床上具有潜在致死性的血管疾病。基质金属蛋白酶（matrix metalloproteinases，MMPs）的表达和活化引起的血管壁弹力纤维降解在动脉瘤的形成中起重要作用。磷脂酰肌醇-3-激酶（Phosphatidylinositol-3-kinase, PI3K）参与一系列细胞的重要功能和信号转导。我们意外发现，PI3K催化亚基p110δ突变失活刺激巨噬细胞MMP-12的表达，造成动脉壁弹力纤维降解和断裂，引起～30%小鼠动脉瘤形成。基于以上工作，我们将p110δ突变失活小鼠与MMP-12-/-杂交，以证明MMP-12在p110δ突变失活小鼠中动脉瘤形成的重要性。鉴于MMP-12启动子中含有AP-1结合位点，我们将在细胞和整体水平研究p110δ突变失活是如何上调MMP-12的表达。进一步在临床动脉瘤病人中筛查是否存在p110δ突变。揭示p110δ在动脉瘤形成中的重要作用和机制。

Aortic aneurysm is an potentially fatal disorder. MMPs(matrix metalloproteinases) ,which degradated elastic fibers of aorta, play an important role in the development of aneurysm.Phosphatidylinositol-3-kinase(PI3K) involved in crucial function and signaling transduction in the cells.We unexpectedly observed that p110δ mutant led to breakage of elastic fibers and stimulated MMP-12 expression.Further studies show that p110δ mutant induced aneurysm(about 30%) .Based on our previous work, we will generate the double-transgenic mice by breeding together two independent lines of C57BL/6J mice carrying either the p110δ mutant or MMP-12-/-,which will demonstrate the key role of MMP-12 in the pathology of aneurysm induced by p110δmutant.Furthermore,since an AP-1 protein binding site in the MMP-12 promoter,we will study how p110δmutant up-ragulate the expression of MMP-12.Finally,screening p110δmutant in patient with aneurysm will confirmed the role of p110δ.