MgONPs调控巨噬细胞免疫功能抑制脱细胞生物瓣钙化的机制研究

免疫原性激活的排斥反应是始动生物瓣钙化的关键原因,制约生物瓣长久耐用性。研发具有免疫调节作用的新型脱细胞生物瓣是抑制免疫排斥反应和钙化的新思路。我们前期证实负载氧化镁纳米颗粒(MgONPs)能提高脱细胞牛心包(dBPs)的力学性能和生物稳定性；且MgONPs调控巨噬细胞糖代谢使其向M2型极化、获得免疫抑制功能；MgONPs还能上调SIRT3表达，并通过SIRT3介导的糖代谢调控巨噬细胞M2型极化；据此，我们提出“MgONPs通过SIRT3介导的糖代谢重编程调控巨噬细胞免疫功能抑制脱细胞生物瓣钙化”的假说。为验证该假说，我们拟采用高通量检测、基因和细胞功能实验分析MgONPs通过SIRT3调控巨噬细胞糖代谢的分子机制、探索MgONPs通过SIRT3介导的糖代谢重编程调控巨噬细胞免疫功能的作用，通过动物实验明确负载MgONPs的dBPs生物瓣的抗钙化作用，为免钙化生物瓣研发提供理论和材料基础。

Immunogenicity activated immunologic rejection is the key mechanism for initiating calcification of bioprosthetic valves, which restricts their long-term durability. Developing the novel decellularized biomaterials with immunomodulatory effect is a promising way to inhibit immune rejection and calcification. In our preliminary studies, we successfully loaded magnesium oxide nanoparticles (MgONPs) on the decellularized bovine pericardium (dBPs). We found that MgONPs improved the mechanical properties and biological stability of dBPs, and induced M2 polarization of macrophages to obtain the immunosuppressive function through regulating glycometabolism. We also found that MgONPs increased the expression of SIRT3, and regulated the glycometabolism and polarization through SIRT3. Accordingly, we proposed a hypothesis that MgONPs regulate macrophage immune function and inhibit the calcification of decellularized bioprosthetic valves through SIRT3 mediated glycometabolic reprogramming. In order to confirm this hypothesis, we will use high-throughput assays, genes and cellular function experiments to analyze the molecular mechanism of MgONPs in regulating the glycometabolism of macrophages through SIRT3, and explore the mechanism of MgONPs in regulating the immune function of macrophages through SIRT3 mediated glycometabolic reprogramming. Finally, the anti-calcification effects of decellularized bioprosthetic valves constructed by dBPs loaded with MgONPs will be confirmed using animal models. By performing this study, we intend to develop the new biomaterial and the theory for construction of free-calcification bioprosthetic valves.