巨噬细胞受到刺激后可融合形成多核巨细胞，此过程与多种慢性炎症性疾病的发生密切相关，但融合的分子机制仍有待研究。最近，细胞表面整合素受体Mac-1被发现直接参与巨噬细胞融合，但它与何种配体结合来介导细胞融合并不清楚。申请人最新的研究发现，Mac-1在体外被金属锰离子激活后会发生自身二聚化，即Mac-1可作为其自身的配体形成受体-配体复合物。据此我们提出一种全新的巨噬细胞膜融合机制的假说，即巨噬细胞在细胞因子的刺激下，其表面的Mac-1被激活，与相邻细胞表面的Mac-1形成二聚体，从而介导巨噬细胞膜融合。我们将通过解析Mac-1二聚化的结构、分析Mac-1二聚体形成的动力学机制、细胞融合实验以及抗体特异性阻断Mac-1二聚体形成等手段，阐明Mac-1介导巨噬细胞融合的详细分子机制，从而加深对细胞膜融合机制的理解，为开发靶向多核巨细胞相关的慢性炎症性疾病的药物提供理论依剧。

Stimulated macrophage fuses to form multinucleated giant cells that closely related to the pathogenesis of several chronic inflammatory diseases. Mac-1, a cell surface integrin receptor, was identified as a direct mediator of macrophage fusion, but which ligand bound to it remains unclear. Recently we discovered that activated Mac-1 dimerized in presence of Mn2+, indicating Mac-1 servers as its own ligand. Therefore, we hypothesized a novel mechanism for macrophage fusion: the stimulation of certain cytokines upon macrophage will trigger Mac-1 activation, which further forms homodimer with neighboring cell surface Mac-1 to mediate cell fusion. We are proposing to elucidate the underlying mechanism of Mac-1 mediated macrophage fusion by structural analysis, kinetics study, cell fusion assay and screening of monoclonal antibody blocking Mac-1 dimerization. This study will expand our knowledge about membrane fusion and provide theoretic evidence for drug development targeting macrophage fusion related inflammation diseases.