低氧应激诱导的SHH通过调控巨噬细胞氧化磷酸化参与瘢痕形成的机制研究

增生性瘢痕严重影响外观，限制关节功能，反复破溃甚至能诱发癌变。由于其形成机制复杂，目前尚无针对性的防治措施。巨噬细胞广泛参与组织修复，但在瘢痕形成中的具体作用尚不明确。申请人前期发现，增生性瘢痕中SHH及下游的表达水平上调，低氧条件下成纤维细胞分泌SHH增多；体外实验证实SHH能够诱导巨噬细胞的氧化磷酸化，在小鼠模型中抑制皮肤氧化磷酸化可显著改善局部纤维化。结合文献回顾，本课题假设：低氧诱导的SHH通过调控巨噬细胞氧化磷酸化，提高成纤维细胞的胶原合成和转分化，进而促进皮肤瘢痕增生。为验证此假说，本课题拟明确成纤维细胞低氧应激对巨噬细胞代谢及表型的调控作用，研究SHH对巨噬细胞氧化磷酸化及瘢痕形成的作用及其潜在机制，验证SHH特异性阻断预防瘢痕的可行性。本研究可阐明巨噬细胞与成纤维细胞的相互调控方式，探索低氧应激下巨噬细胞及SHH在瘢痕增生过程中的潜在作用，为临床增生性瘢痕的防治提供新思路。

Hypertrophic scar often results in severe cosmetic defect, limitation of joint movement, ulceration, even canceration. Due to the undiscovered mechanism, there is no specific strategy for the prevention and treatment of hypertrophic scar. Macrophage is widely involved in tissue repair process, but the exact role of macrophage in hypertrophic scar formation is still unclear. We found that expressions of SHH and the downstream molecular were elevated in hypertrophic scar tissue, and SHH expression was increased in fibroblasts exposed to hypoxia. In vitro study proved that SHH was able to induce oxidative phosphorylation in macrophage, and oxidative phosphorylation inhibitor alleviated fibrosis in mice skin wound. Based on these results and literature review, we hypothesize that hypoxia induced SHH might modulates oxidative phosphorylation in macrophage, elevates collagen synthesis and trans-differentiation of fibroblast, and leads to hypertrophic scar. To verify this hypothesis, this project will detect the way hypoxia-stimulated fibroblast regulating the metabolism and phenotype of macrophage, study the effect and underlying mechanism of SHH on macrophage oxidative phosphorylation and scar fibrosis, and verify the feasibility of scar prevention by SHH-specific block. This project aims to demonstrate the interrelation of macrophage and fibroblast, explore the potential role of macrophage and SHH in scar formation under hypoxia, and provide new insight into scar prevention and treatment.