过氧化物酶体增殖物激活受体-γ与睑板腺功能障碍的关系及其机制

Meibomian gland dysfunction (MGD) is a chronic, diffuse abnormality of the meibomian glands,characterized by ductal obstruction and/or qualitative/quantitative changes in the glandular secretion, resulting in tear film instability and evaporation. MGD is thought to be the major cause of dry eye syndrome with high prevalence in clinical practice. However, limited information is known about the physiological control of the meibomian gland in health or disease, as well as the relationship between MGD and other ocular surface diseases, leading to the unsatisfactory in MGD management. Previous evidences have revealed a higher incidence of hyperlipidemia in MGD patients, indicating that hyperlipidemia may affect on the meibomian gland via certain mechanism. Given the fact that peroxisome proliferator-activated receptor-γ (PPAR-γ) is considered as the major signals controlling the lipid synthesis and sebaceous gland function and is positively expressed in meibomian gland epithelial basal cell, we supposed that PPAR-γ may play a critical role in the meibomian gland function. This project attempts to investigate the importance and relationship between MGD and several common ocular surface diseases, elucidate the exact effects of hyperlipidemia on basic cell function, lipid synthesis and inflammatory responses in cultured human meibomian gland epithelial cell and PPAR-γ knockout mice, as well as the role of PPAR-γ in this process, conceiving the perspectives of PPAR-γ agonists in the treatment of patients with MGD. Besides, the feasibility of PPAR-γ knockout mice as an animal model of MGD would be evaluated. On the whole, the implementation of this project would probably promote scientific research in this area and bring great economic and clinical value.

睑板腺功能障碍（MGD）是各种慢性、弥漫性睑板腺异常的统称，以腺体阻塞和（或）腺体分泌物的质或量异常为一般特征，可致泪膜不稳定和蒸发过强，是临床干眼及各种眼表不适的常见而易忽视的原因的。然而，当前对睑板腺生理及病理调控机制及其与眼表其它疾病关系的理解十分匮乏，极大制约了治疗的针对性。研究已证实，高脂血症是MGD的重要危险因素之一,提示脂质代谢异常可能与睑板腺功能障碍有关。过氧化物酶体增殖物激活受体-γ（PPAR-γ）是调控脂质合成和代谢的关键通路之一，在睑板腺上皮细胞中高表达，故推测其可能是调控睑板腺结构功能的关键因子。本研究内容包括探讨睑板腺及其功能障碍的普遍性及其与常见眼表疾病的相关性，PPAR-γ通路对体外培养睑板腺上皮细胞以及活体小鼠睑板腺的基本功能、脂质分泌及炎症因子水平的影响，构建基于PPAR-γ基因敲除的睑板腺功能障碍小鼠模型。因此，本项目的实施具有重大的科学意义和临床价值。

睑板腺生理及病理调控机制及其与眼表其它疾病关系的理解还十分匮乏，制约了治疗的针对性。过氧化物酶体增殖物激活受体-γ（PPAR-γ）是调控脂质合成和代谢的关键通路之一，在睑板腺上皮细胞中高表达，可能是调控睑板腺结构功能的关键因子。本研究的主要内容包括探讨睑板腺及其功能障碍的普遍性及其与常见眼表疾病的相关性，PPAR-γ通路对体外培养睑板腺上皮细胞以及活体小鼠睑板腺的基本功能、脂质分泌及炎症因子水平的影响，构建基于PPAR-γ基因敲除的睑板腺功能障碍小鼠模型。在项目进行过程中，已经有新文献报道了高糖环境对体外培养睑板腺上皮细胞增殖、分化有脂质分泌能力的影响及其部分机制，因此本研究主要方向调整为探讨多种临床疾病状态与睑板腺形态功能之间的内在联系。重要结果包括：发现糖尿病、翼状胬肉、季节性过敏性结膜炎等数种常见眼表疾病状态下的泪膜异常均与睑板腺功能障碍存在密切相关性；其中，糖尿病对睑板腺形态功能的影响在血糖水平正常、糖化血红蛋白水平仍较低的情况下已经存在。此外还发现高糖环境对体外培养睑板腺上皮细胞的增殖及脂质分泌能力具有一定影响。这些发现进一步表明睑板腺的形态功能变化在多种眼表疾病中存在至关重要的作用，它可能是疾病的表征之一，也可反过来成为某些并发症的原因。