Meibogenesis in Health, Disease, and Aging

项目总结：我们项目的目标是研究诱导和诱导的分子机制。 人和小鼠颧板内的眉板腺(MG)的减数分裂。 微发育的定义是一系列复杂的分解代谢和合成代谢反应，以及相应的调节 以及信号机制，这些机制导致了一种叫做meiban的全分泌分泌的形成。美宝是独一无二的 主要由极长链和支链蜡酯、胆固醇酯、 以及一系列其他更复杂的化合物。蜂蜜对眼睛健康至关重要，因为它形成了一种保护性的 将眼睛表面与环境隔离的一层，通过改变屈光度来提高视力 角膜的特性。在正常情况下，蜂蜜的脂组成非常保守，这意味着 MG的脂平衡通常处于严格控制之下，其调节机制尚不明确。然而， 一种名为MG功能障碍(MGD)的MG病理会导致尿嘧啶产量下降或不良变化 在其组成中，或两者兼而有之，对眼表生理、视力和生活质量产生负面影响 将军。MGD是一种被称为干眼综合征(DES)的广泛疾病的主要促成因素。MGD 而DES影响了全球高达40%的总人口，对老年人的影响不成比例。此前，我们 证明小鼠是研究人类MG胚胎发育的可靠模型。使用不同的行 对于突变的小鼠，我们已经建立了参与小染色体发育的主要基因和酶。然而， 其启动和调控机制尚不清楚。以前在细胞中诱导小核发育的尝试 培养(如永生化的人MG上皮细胞)失败了，因为没有产生眉毛脂 在任何测试条件下。因此，我们的目的是阐明小胚胎发生的诱导和衰退的机制。 通过进行转录，脂组，免疫组织化学和生理特性的活体 发展和老化MG，以经历出生前和出生后发育和老化的小鼠为主要研究对象 动物模型，不同年龄的人体受试者。这些实验应该能让我们确定 发育、成熟和衰老MG的变化时间表，以及总体上与MG转录组相关的时间线； 小胚胎发育的关键基因，以及特定的酶及其相应的表达水平 脂肪产品。将特别考虑同时：1)在MG中高表达的基因， 2)编码已知的控制组织生长、细胞分化和脂质的信号因子 MG和/或其他组织中的动态平衡，以及3)其表达水平在 发育和老化的MG。这些结果将为今后的深入研究提供至关重要的信息 MG生理学的常模和病理学。

PROJECT SUMMARY: The goal of our project is to investigate the molecular mechanisms of induction and decline of meibogenesis in Meibomian glands (MG) embedded in tarsal plates of humans and mice. Meibogenesis is defined as an intricate array of catabolic and anabolic reactions, and corresponding regulatory and signaling mechanisms, that lead to formation of a holocrine secretion called meibum. Meibum is a unique lipid secretion that is comprised primarily of extremely long chain and branched wax esters, cholesteryl esters, and a range of other, more complex, compounds. Meibum is vital to the ocular health as it forms a protective layer that isolates the surface of the eye from the environment, and improves vision by changing the refractive properties of the cornea. Lipid composition of meibum is very conservative in normal conditions, implying that lipid homeostasis of MG is typically under tight control of yet to be identified regulatory mechanisms. However, a MG pathology called MG dysfunction (MGD) results in a decline in meibum production, or adverse changes in its composition, or both, negatively affecting the ocular surface physiology, vision, and quality of life in general. MGD is a major contributing factor to a widespread condition called Dry Eye syndrome (DES). MGD and DES affect up to 40% of the general population worldwide, disproportionately affecting elderly. Earlier, we demonstrated that mice are credible models of human MG for studying meibogenesis. Using various lines of mutant mice, we have established major genes and enzymes that are involved in meibogenesis. However, the mechanisms of its initiation and regulation remain unknown. Previous attempts to induce meibogenesis in cell cultures (such as immortalized human MG epithelial cells) failed, as no meibomian lipids have been produced in any tested conditions. Thus, our aim is to elucidate the mechanism of meibogenesis induction and decline in vivo by conducting transcriptomic, lipidomic, immunohistochemical, and physiological characterization of developing and aging MG, using mice that undergo prenatal and postnatal development and aging as primary animal model, and human subjects of different ages. These experiments should allow us to determine a timeline of changes in developing, maturing, and aging MG, and correlate MG transcriptome in general, and key genes of meibogenesis specifically, with the expression levels of specific enzymes and their corresponding lipid products. Special consideration will be given to genes that simultaneously: 1) are highly expressed in MG, 2) encode signaling factors that are already known to control tissue growth, cell differentiation and lipid homeostasis in MG and/or other tissues, and 3) whose expression levels undergo significant changes in developing and aging MG. These results will provide critically important information for future in-depth studies of MG physiology in the norm and pathology.