Sox9在睑板腺功能障碍中的作用及机制研究

Meibomian gland dysfunction (MGD) may be the leading cause of dry eye disease throughout the world. However, its pathogenesis remains unknown. As epithelial appendages of the skin, Meibomian glands and hair follicle/sebaceous glands are developmentally similar and share common characteristics. Sox9 is required for the formation and function of hair follicle and sebaceous glands. Our previous data showed that FGF signaling activated Sox9 and extracellular matrix (ECM) pathway to control the formation of murine lacrimal and Harderian glands. And Sox9 conditional knockout mice displayed the defect of Meibomian glands, including the decreasing number of glands and the atrophy of acini. Therefore, we propose that Sox9 and FGF signaling may affect the physiology of Meibomian glands and the pathogenesis of MGD. In this study, we will investigate the role of Sox9 in the pathogenesis of MGD through conditional deletion of Sox9 in mice and transfections with Sox9-siRNA and Fgfr2-siRNA in primary cultured murine Mebomian gland epithelial cells. And we will also conduct the intraductal Meibomian gland probing and injection of Sox9 plasmid to treat rabbit MGD model, which aims to explore the new strategy for the treatment of MGD. This project will provide the data for elucidating the pathogenesis of MGD and a novel insight into the specific-target therapy for MGD.

睑板腺功能障碍（MGD）所致干眼症的发病率增加，但其发病机制尚不明确。睑板腺为全身最大的皮脂腺，与毛囊/皮脂腺有相似的发育模式及组织特性，Sox9是参与调控毛囊/皮脂腺形成与功能的关键因子。我们前期研究结果发现眼表上皮Sox9条件性基因敲除（Sox9CKO）小鼠的睑板腺腺体数目减少、腺泡萎缩，与MGD的睑板腺缺失体征相似；同时FGF信号通过激活Sox9及细胞外基质通路调控小鼠泪腺和哈氏腺的形成。现推测Sox9通过FGF信号通路调控睑板腺的形成与功能，并参与MGD的发病机制。本课题将通过建立Sox9CKO小鼠及小鼠睑板腺上皮细胞分别转染Sox9-siRNA及Fgfr2-siRNA实验探讨Sox9及FGF信号通路在MGD中的作用及分子机制，并探索睑板腺腺管内注射转染Sox9质粒对兔MGD模型的治疗效应。结果对揭示MGD的病因及发病机制有重要意义，且可为MGD所致干眼症的治疗提供一种新的策略。

睑板腺功能障碍(MGD)是干眼最常见的类型，但其发病机制尚不明确。本研究项目旨在探讨睑板腺形成与功能的分子机制以及MGD的发病机制。研究结果显示Sox9条件性基因敲除小鼠的睑板腺腺体数目减少、腺泡萎缩，Sox9调节眼睑组织Sfrp1的表达，但不调节Ptch1、Krt4和Krt12的表达。Sox10条件性基因敲除小鼠的睑板腺腺泡结构欠明显。结果提示Sox9影响胚胎期部分睑板腺腺体出芽且睑板腺腺泡的形成，Sox10影响睑板腺腺泡的形成。此外，Edar及Edaradd表达于正常小鼠睑板腺芽的上皮细胞中，提示Edar及Edaradd可能与睑板腺的形成相关。先天性泪腺发育缺陷的患者表现为泪液水液的缺乏伴有睑板腺的缺失及眼表上皮的损伤，但基因测序没有找到如FGF10、SOX9及SOX10 等相关基因异常，同时还对其泪液蛋白质组的分析等，希望找到针对性的治疗方法。本项目研究结果对揭示睑板腺形成与功能的分子机制以及MGD的发病机制有重要意义。