巨噬细胞通过胞葬作用清除凋亡细胞，具有抑制自身免疫和慢性炎症的作用，影响多发性硬化等自身免疫性疾病的发生和发展。前期研究显示活性维生素D可以显著上调基因ASAP2的表达，而ASAP2是多发性硬化风险基因且参与细胞骨架的调节。申请人还发现活性维生素D潜在提高了巨噬细胞的胞葬能力。因此假设：活性维生素D（1,25(OH)2D3）通过上调ASAP2表达促进巨噬细胞胞葬作用。申请人发现在ASAP2基因内有维生素D受体结合的超级增强子存在，被PU.1预结合，且该类超级增强子富集RUNX3结合基序。因此拟重点研究巨噬细胞中活性维生素D通过其受体与超级增强子、PU.1和RUNX3共同调节ASAP2转录的分子机制。并进一步通过小鼠EAE模型验证多发性硬化和胞葬以及ASAP2表达的相关性。本研究将揭示活性维生素D调节胞葬表型的通路机制，阐明ASAP2基因的转录机制，并为多发性硬化胞葬表型的深入研究奠定基础。

Normal macrophage efferocytosis can inhibit autoimmune and chronic inflammation, which underlies the aetiology and development of autoimmune diseases including Multiple Sclerosis. It has been found that 1,25(OH)2D3 can upregulate the expression of gene ASAP2, which is a Multiple Sclerosis risk gene and involved in regulating cytoskeleton. The applicant also found that 1,25(OH)2D3 potentially increased the efferocytosis of macrophages. Therefore, we hypothesize that 1,25(OH)2D3 can promote macrophage efferocytosis by upregulating the expression of ASAP2. The applicant also found there was a super-enhancer region bound by vitamin D receptor (VDR) in gene ASAP2, which has been pre-occupied by PU.1. And this class of super-enhancers is enriched for RUNX3 motif. Based on it, this project plan to further focus on the interaction between Vitamin D receptor, super-enhancer, PU.1, and RUNX3, which underlies the molecular mechanism of ASAP2 transcription. Furthermore, we plan to verify the association between Multiple Sclerosis, efferocytosis, and ASAP2 by using mouse EAE model. This research will reveal the mechanism of 1,25(OH)2D3 in regulating efferocytosis, clarify the transcriptional mechanism of ASAP2, and lay the foundation for further exploration on efferocytosis in Multiple Sclerosis.