THY1通过调控皮肤脂肪抵抗纤维化的性别差异机制研究

皮肤纤维化会导致毛囊萎缩、瘢痕增生、伤口修复失调等健康问题，多种皮肤纤维化疾病存在性别差异，内在机制尚不明确。皮肤脂肪具有抗菌、促伤口修复和毛发生长等活性，是维持皮肤稳态的新型调控单元，皮肤纤维化病变会造成皮肤脂肪丢失，体内实验可见雌鼠比雄鼠更加能抵抗老化引起的皮肤脂肪减少，表达更低的纤维化相关蛋白。申请人前期研究发现THY1高表达于雌鼠皮肤，敲除Thy1能抑制皮肤脂肪增生。THY1是锚定于质膜的糖蛋白，高表达于脂肪前体细胞，已报道该蛋白与多条促纤维化信号相关，我们推测THY1是介导皮肤脂肪分化和纤维化平衡的关键因子。本项目将在此基础上，以单细胞转录组测序结合小鼠皮肤纤维化模型为主要手段，深入研究THY1如何通过调控皮肤脂肪抑制纤维化的内在机制，以及性激素信号如何影响THY1功能从而介导皮肤纤维化的性别差异，研究成果将揭示皮肤纤维化相关疾病性别二态性的内在病理机制，为疾病治疗提供新的方向。

Skin fibrosis can cause health problems such as hair follicle atrophy, scar hyperplasia, wound repair disorders, etc. There are sexual differences in a variety of skin fibrosis-related diseases, and the underlying mechanism remains poorly understood. Dermal fat, also called skin fat, which is a new type of regulation unit that maintains skin homeostasis, plays active roles in various physiological and pathological processes of skin, such as the protection against skin infection, wound healing, regeneration of hair follicles, etc. Skin fibrosis can lead to the loss of skin fat. The skin of female mice is more resistant to age-related fat loss and has less expression of fibrosis related proteins compared to male skin in vivo, suggesting that dermal fat has sexual dimorphism and is tightly associated with fibrotic skin lesions. Here, by RNA transcriptome sequencing and immunohistochemistry staining, we found that THY1 is highly expressed in the skin of female mice, and ablation of Thy1 can inhibit expansion of skin fat and promote a pro-adipogenic to pro-fibrotic switch in dFBs. THY1 is a glycoprotein anchored to the plasma membrane and highly expressed in adipocyte precursor cells. It has been reported that THY1 is associated with multiple pro-fibrotic signaling pathways. We have supposed that THY1 is a key factor that mediates the balance between skin adipogenesis and skin fibrosis. Accordingly, we will further investigate the underlying mechanisms of how THY1 inhibits fibrosis by regulating skin fat and how sex hormone signals mediates sexual difference of skin fibrosis through affecting the function of THY1. Single-cell transcriptome sequencing combined with experimental mouse model of bleomycin-induced skin fibrosis would be applied to this project. The results may reveal the pathogenesis of sexual dimorphism in fibrotic skin diseases and provide new insights for diseases treatment.