冠状动脉疾病是导致病人死亡的主因之一。GWAS研究发现，PHACTR1与冠状动脉疾病显著相关。但其在动脉粥样硬化中的作用尚无报道。本课题组建立了PHACTR1全身和条件敲除小鼠。前期结果发现，全身敲除小鼠发育正常，但活体显微实验显示敲除小鼠肠系膜动脉单核细胞粘附明显减弱。离体条件下， 敲减PHACTR1明显抑制TNF-α诱导的内皮细胞激活和NF-κB信号通路。 因此，提出假设PHACTR1通过激活NF-κB信号通路，促进内皮细胞活化和单核细胞粘附，从而导致动脉粥样硬化的发生和发展。为验证该假设，我们首先研究PHACTR1对内皮细胞激活的作用和机制。然后，用PHACTR1内皮特异性敲除ApoE-/-小鼠来研究PHACTR1对动脉粥样硬化的作用。最后，我们用全身PHACTR1敲除 ApoE-/-小鼠来进一步验证PHACTR1对动脉粥样硬化的影响。这一研究将为冠心病治疗提供新机制、新靶标。

Coronary artery diseases are leading cause of death. GWAS studies demonstrate that several SNPs of PHACTR1 robustly associated with coronary artery diseases. However, to date no reports on PHACTR1’s biological function. The role of PHACTR1 in development and progress of atherosclerosis is still unknown. Thus, we generated global PHACTR1 knockout (gPHACTR1-KO) mice and conditional PHACTR1 KO mice. gPHACTR1-KO mice develop normal. But introvital microscopy experiments show decreased adhersion of monocyte to the mesenteric artery. In vitro, depletion of PHACTR1 siginicantly inhibits TNF-α-induced endothelial activation, activation of NF-κB signaling and Thp1 adhesion to endothelial cells. Therefore, we hypothesize that PHACTR1 promotes the deveopment and progress of atherosclerosis by increasing endothelial activation through NF-κB signaling. To test our hypothesis, we propose 3 aims. Aim 1. Determine the role of EC PHACTR1 on endothelial activation and its mechanisms. Aim2. Define the effect of PHACTR1 on the deveopment and progress of atherosclerosis using ec PHACTR1-KO ApoE-/- mice. Aim3. To further confirm the role of EC PHACTR1, we will determine the effect of PHACTR1 on the deveopment and progress of atherosclerosis using gPHACTR1-KO ApoE-/- mice. Our study will shed new lights on the mechansims and treatment of atherosclerosis.