肠黏膜屏障（IEB）是机体防御的重要屏障，在前期研究中，我们首次发现骨形态蛋白（BMP）信号通路的激活与IEB功能损伤密切相关，但其机制不清楚，近来研究表明：NRAGE在BMP激活NF-κB信号通路中可能扮演着关键角色，同时NRAGE的上调可干预细胞粘附分子E-cadherin的表达与分布。由此我们推测：NRAGE通过激活NF-κB来干预IEB关键粘附分子表达与分布可能是BMP介导IEB损伤的关键机制。本研究拟采用NRAGE kockout 鼠模型及利用SiRNA阻断肠上皮细胞中NRAGE，通过给予或激活BMP观察对NF-κB激活状况及肠粘膜结构及功能的影响，并利用NRAGE的功能区（重复区域）设计小分子的多肽，进一步明确在缺血再灌注条件下其对IEB的保护作用，初步阐明BMP通过NRAGE信号诱导肠粘膜屏障损伤的机制，为IEB功能障碍的治疗寻找新的靶点。

Intestinal epithelial barrier (IEB) is an important defense barrier. Our previous study has found that the activation of BMP signaling pathway is closely related to the damage of IEB functions. However, the mechanisms remain unclear. Recent study shows that NRAGE may play an important role in the activation of NF-κB by BMP signaling pathway, and its up-regulation excerts negative effects on the expression and distribution of the E-cadherin. Based on the preliminary study, we hypothesize that BMP distribupted the expression and distribution of the key adherens junctions and tight junction proteins of IEB through NRAGE may be the key mechanism through which BMP mediated IEB founction damage. This study will further detect NF-κB activation and its effects on structure and function of IEB by the administration of BMP in the NRAGE knockout mice model and in IEC using SiRNA blocking NRAGE expression, in vivo and vitro, meanwhile we will design a small molecular peptides which based on NRAGE protein functional areas (repeat domain) to detect its effects on the NF-κB activation and the protection on intestinal epithelial barrier in ischemical reperfusion injury mice. This project will be carried out to analyze the possible mechanism of NRAGE involved in the IEB injury and to find a novel therapeutic target for IEB dysfunction.