mTORC1-LL37正反馈环路在玫瑰痤疮发病中的作用及机制研究

玫瑰痤疮是一类慢性炎症性皮肤病，其发病机制尚不明确。免疫和神经血管功能失调是诱发该病的重要因素，且表皮抗菌肽LL37过度表达在该过程中发挥关键作用。我们前期研究发现mTORC1在玫瑰痤疮患者和小鼠模型皮损（特别是表皮）中均过度活化；mTORC1表皮敲除或药物抑制均可改善小鼠玫瑰痤疮样表型，反之则促进其发病；且在角质形成细胞中mTORC1可与LL37形成正反馈调控环路。故推测mTORC1-LL37正反馈环路在玫瑰痤疮发病中起关键作用。本研究将利用mTORC1表皮敲除鼠进一步确定其在该病中的作用；通过基因功能缺失或获得、蛋白质谱与免疫共沉淀等实验完善该正反馈调节环路，并研究介导LL37激活mTORC1的可能受体及结合位点；然后利用玫瑰痤疮患者及敲除鼠皮损进行转录组测序筛选关键基因，研究其具体机制。本研究旨在揭示mTORC1-LL37正反馈环路在玫瑰痤疮发病中的作用机制，为其临床治疗提供新方向。

Rosacea is well established as a chronic inflammatory skin disease, whose pathophysiology remains largely unclear. Abnormalities in the innate immune system and neurovascular dysregulation have been considered to be primarily implicated in the development of rosacea, and over-production of cathelicidin LL37 plays a key role in these processes. Our previous data showed that mTORC1 signaling is hyperactivated in skin lesions (especially in epidermis) of both rosacea patients and mouse model. By employing LL37-induced rosacea mouse model, we showed that mTORC1 deletion in epithelium or pharmacological inhibition significantly alleviated the rosacea-like phenotypes. Conversely, hyperactivation of mTORC1 signaling exacerbated the development of rosacea. Moreover, we demonstrated that by binding to TLR2, cathelicidin LL37 regulates mTORC1 signaling through a positive feedback circuit in keratinocytes. So, we anticipated that mTORC1 signaling is pivotal in the pathophysiology of rosacea. Here, by using an inducible conditional gene targeting strategy to ablate mTORC1 in adult skin epithelium, we will further figure out the role of mTORC1 signaling in the development of rosacea. We will clarify the positive feedback circuit between mTORC1 and cathelicidin LL37 through both gain- and loss-of-function studies and protein mass spectrometry and co-immunoprecipitation. Then, using RNA-sequencing analysis, we will unearth differentially expressed genes and signaling pathways in skin lesions of rosacea patients and mouse models. The function and regulatory mechanisms of those genes or pathways will be further identified in vivo and in vitro. In summary, our findings will support mTORC1 signaling as a novel determinant in rosacea and hence a potential new therapeutic target.