血管紧张素II诱导的心脏炎症反应参与心室重构，但它如何引发炎症尚不完全清楚。TLR2是天然免疫中的重要模式识别受体，已发现它与AngII诱导的炎症和心室重构有关，但其参与的机制尚不明确。我们前期研究中，确证了TLR2全身敲除显著缓解小鼠中AngII诱导的心脏炎症和纤维化，且心脏中的TLR2主要定位于心肌细胞；体外实验中发现AngII可与心肌细胞膜上的TLR2发生直接结合，且该过程与其经典受体AT1无关。因此，我们提出假设：TLR2可能是AngII的一种非经典受体，AngII被心肌细胞膜上的TLR2直接识别，结合并激活TLR2，引发心脏炎症反应及随后的心室重构。本项目希望利用AngII-rhTLR2蛋白复合物共结晶技术、CRISPR/Cas9技术、心脏TLR2特异性敲除小鼠和小鼠骨髓移植模型等系列的生物学实验，证实上述科学假设，为缓解心室重构及心力衰竭阐明新的分子机制、提供新的治疗靶点。

Although angiotensin II (AngII) has been proved to play important roles in the pathological process of cardiac remodeling, the underlying mechanism is still unknown. TLR2 is one of the pattern recognition receptors in innate immunity, which has been found to involve in this process. However, how TLR2 regulates AngII-induced cardiac inflammation and remodeling is yet fully studied. In our previous study, our data show that TLR2 is mainly expressed in cardiomyocytes, and whole body knockout of TLR2 significantly reduced AngII-induced cardiac inflammation and fibrosis in the mouse model. Moreover, our in vitro data show that AngII could directly bind to TLR2 of cardiomyocytes in an AT1-independent manner. Thus, we hypotheses that TLR2 may be a non-classic AngII receptor. AngII can directly bind to TLR2 and then activate the TLR2 signaling pathway in cardiomyocytes, inducing cardiac inflammation and remodeling eventually. In this study, we plan to perform a series of experiments, including AngII-rhTLR2 protein complex co-crystallization, silencing TLR2 via CRISPR/Cas9, cardiac specific TLR2 knockout mice development and bone marrow transplantation, to evaluate and confirm the above hypothesis. The completion of these studies will demonstrate novel molecular mechanisms in the pathology of cardiac remodeling, and also providing a new target for the treatment of cardiac failure.