Wnt5a-Ror2介导的成纤维细胞分化在心脏重构中的作用及机制研究

心脏重构是心衰发生发展的病理生理基础，成纤维细胞(CFs)向肌成纤维细胞(MFB)的分化平衡是调控心脏重构的关键，但机制尚不清楚。申请人前期发现中性粒细胞来源的Wnt5a导致压力超负荷后病理性心脏重构，但在后续Wnt5a全敲小鼠中得到相反表型，结合预实验发现CFs是Wnt5a在受损心肌的主要来源，提示CFs来源Wnt5a可能在心脏重构中发挥重要作用；Ror2是介导非经典PCP通路的Wnt5a受体，我们发现Ror2在受损心肌被诱导表达于MFB，且Ror2敲除与Wnt5a敲除均导致CFs异常增殖和病理性心脏重构，结合预实验发现Ror2在CFs中介导Wnt5a-PCP信号，我们推测：CFs来源的Wnt5a通过Ror2受体调节CFs分化促进心脏适应性重构。本项目拟利用CFs条件性敲除和过表达小鼠模型，在体与离体研究CFs分化以及心脏重构表型，有望从非经典Wnt信号角度揭示心脏重构的新型调控机制。

Cardiac remodeling is the pathophysiological basis for the development of heart failure. The balance of differentiation of fibroblasts (CFs) to myofibroblasts (MFB) is a key step in regulating cardiac remodeling, however, its regulatory mechanism is still unclear. The applicant previously found that neutrophil-derived Wnt5a lead to pathological cardiac remodeling after pressure overload, unexpectedly, the opposite phenotype was obtained in subsequent studies using Wnt5a global knock-out mice, considering preliminary experimental findings that CFs are the main source of Wnt5a in damaged myocardium, CF-derived Wnt5a was suggested to play an important role in cardiac remodeling; Ror2 acts as Wnt5a receptor that mediates non-canonical PCP signaling pathway. Preliminary experiments have found that Ror2 is induced and expressed in MFB in damaged myocardium, moreover, both Ror2 knockout and Wnt5a knockout resulted in CFs hyper-proliferation and pathological cardiac remodeling, considering the direct regulatory effect of Ror2 on Wnt5a-mediated PCP signaling pathway, we speculate that CF-derived Wnt5a regulates the balance of CFs differentiation and promotes the adaptive cardiac remodeling through Ror2 receptor. This project intends to use the mouse pressure-overload model, combined with CFs conditional knockout and overexpression methods in vivo and in vitro experiments, to study the CFs proliferation, differentiation and cardiac remodeling phenotype. It is expected to discover a new mechanism of cardiac remodeling from the perspective of non-canonical Wnt signaling pathways.