环状RNA（hsa_circ_005219）通过调控骨桥蛋白参与玫瑰痤疮发病的作用机制研究

Rosacea is a common chronic inflammatory disease. Osteopontin (OPN) was identified in many cell types in the immune system, which was presumably involved in many aspects of pathogenesis of immune mediated inflammatory diseases. However, it remains unclear how the expression of OPN was regulated. In our previous study, we found that the expression of circular RNA hsa_circ_005219 was increased in the skin lesions of rosacea, which regulated OPN expression through competitive binding of miR-335-5p. The expression pattern of hsa_circ_005219 was positively correlated with that of OPN. High levels of hsa_circ_005219 would arrest miR-335-5p, resulting in the decrease of free miR-335-5p in the cell. Consequently, low level of miR-335-5p led to the upregulation of OPN expression. In this study, the regulation of hsa_circ_005219 on OPN will be further confirmed, and the role of hsa_circ_005219 in the onset of rosacea will be explored at the molecular level, cellular level and animal level extensively. Hsa_circ_005219 knockout mice will be used as the induced rosacea model. In a word, we aim to clarify the pathogenic pathway of “hsa_circ_005219 — miR-335 — OPN — rosacea”, and provide new clues for the extensive understanding of rosacea.

玫瑰痤疮（Rosacea）是一种累及面部血管及毛囊皮脂腺的慢性炎症性疾病，目前认为玫瑰痤疮发生发展与皮肤免疫系统和神经血管系统的功能失调有关。本课题组的前期研究发现，环状RNA（hsa_circ_005219）是调控骨桥蛋白（osteopontin，OPN）表达的重要因素之一。Hsa_circ_005219在玫瑰痤疮的皮损组织中表达升高，并通过竞争性结合miR-335调控OPN的表达，其与OPN的表达水平呈现明显的相关性。因此，本项目拟在前期研究基础上，进一步明确hsa_circ_005219对OPN的调控作用，并以hsa_circ_005219基因敲除小鼠作为主要模型，在分子、细胞和整体动物水平探讨hsa_circ_005219参与玫瑰痤疮病理过程的具体作用机制。本项目旨在完善“hsa_circ_005219—miR-335—OPN—玫瑰痤疮”这一致病途径，为玫瑰痤疮的机制研究提供线索。

玫瑰痤疮（Rosacea）是一种慢性炎症性皮肤病，其特征是反复出现潮红或持续性红斑、丘疹、脓疱和毛细血管扩张。先天免疫系统失调是导致玫瑰痤疮的发病因素。骨桥蛋白（OPN）是一种由多种组织和细胞表达的磷酸化糖蛋白，在先天免疫应答中发挥重要作用。本项目的前期工作发现在玫瑰痤疮患者的皮损中OPN的表达上调，暗示OPN可能通过影响先天免疫细胞的功能参与玫瑰痤疮的炎症反应。本项目发现环状RNA hsa_circ_005219在玫瑰痤疮皮损中表达增加，并通过竞争性结合miR-335调节OPN的表达。hsa_circ_005219的表达模式与OPN的表达模式呈正相关。高水平的hsa_circ_005219可抑制miR-335，导致细胞中游离miR-335的减少，而低水平的miR-335导致OPN表达上调。hsa_circ_005219敲除小鼠诱导玫瑰痤疮模型后其红斑等症状有所缓解。总之，本项目在分子水平、细胞水平和动物水平上揭示hsa_circ_005219通过调控OPN的表达参与玫瑰痤疮的先天免疫反应的作用机制。