Age-Related Meibomian Gland Dysfunction

项目摘要/摘要 这个项目的长期目标是了解与年龄相关的眉毛腺功能障碍的机制。 (MGD)和蒸发性干眼。我们实验室最近发表的使用受激拉曼的研究 光谱学(SRS)评估眉板腺脂质质量(MEIBUR)表明， 正常腺体内正常腺体从腺泡向腺泡递增时的蛋白质含量 孔口。这一发现表明，正常的小细胞分化需要去除细胞外的蛋白质。 在释放到泪膜之前。此外，我们的实验室已经表明，暴露在低湿度下的小鼠 环境压力，已知的诱发EED的迹象，显示出显著的眉毛过度增殖。 腺体中有蛋白质滞留，表明环境应激导致异常或 小细胞分化不完全。这些发现支持两种不同的假说 MGD的发生：1)环境应激或老化导致巨噬细胞不完整或异常 分化导致蛋白质滞留在蜂蜜中，失去脂质流动性和浓缩。和2) 衰老和/或反复的环境应激导致蜂窝干细胞和蜂窝细胞枯竭 腺体脱落。这些假说强调了关于眉板腺的两个主要认识空白。 功能：Gap1，而脂质成分及潜在的激素等因素为MGD的危险因素 已经进行了深入的研究，但对小细胞分化以及细胞和分子机制知之甚少。 控制这一过程的机制。GAP2，虽然眉毛腺腺泡细胞的周转率 已经研究过了，眉板腺干细胞的存在仍然存在争议，而且 环境压力、衰老和性别都是未知的。以下具体目标将检验我们的假设和 探索这些知识的差距：1)用SRS表征表达的蛋白质/脂比(P/L) EED患者体征及症状与P/L比值的相关性研究 临床研究中的严重程度。2)确定小细胞分化的细胞和分子机制 体外解体及测定环境应激、衰老和性别对巨噬细胞的影响 体内分化。3)通过谱系追踪确定小细胞和导管上皮更新的来源 并确定环境应激、年龄和性别对眉腺导管上皮细胞和 用五彩纸屑和H_2B-GFP/K5tTA小鼠更新巨噬细胞并进行IT重建。

Project Summary/Abstract The long-term goal of this project is to understand the mechanism of age-related meibomian gland dysfunction (MGD) and evaporative Dry Eye EDED. Recent published studies from our laboratory using Stimulated Raman Spectroscopy (SRS) to evaluate meibomian gland lipid quality (meibum) indicate that there is a decrease in protein content of normal meibum within individual glands as it moves progressively from the acinus to the orifice. This finding suggests that normal meibocyte differentiation involves removal of protein from meibum prior to release onto the tear film. Additionally our laboratory has shown that mice exposed to low humidity environmental stress, known to induce signs of EDED, display marked hyperproliferation of the meibomian gland with retention of protein in the meibum lipid suggesting that environmental stress induces abnormal or incomplete meibocyte differentiation. These findings support two alternative HYPOTHESES for the development of MGD:1) Environmental stress or aging leads to incomplete or abnormal meibocyte differentiation causing retention of protein in meibum, loss of lipid fluidity and inspissation. And 2) Aging and/or repeated environmental stress leads to depletion of meibocyte stem cells and meibomian gland dropout. These hypotheses emphasize two MAJOR GAPS in knowledge regarding meibomian gland function: GAP1, while the lipid composition of meibum and potential hormonal and other risk factors for MGD has been intensively studied, little is known regarding meibocyte differentiation and the cellular and molecular mechanisms that control this process. GAP2, although the turnover rate for the meibomian gland acinar cells has been studied, the presence of meibomian gland stem cells remains controversial and the effects of environmental stress, aging and sex are unknown. The following Specific Aims will test our hypotheses and explore these GAPS in knowledge: 1) Characterize using SRS the protein to lipid ratio (P/L) in expressed meibum from human subjects exhibiting signs and symptoms of EDED and correlate P/L ratio to EDED/MGD severity in a clinical study. 2) Identify the cellular and molecular mechanism of meibocyte differentiation and disintegration in vitro and determine the effects of environmental stress, aging and sex on meibocyte differentiation in vivo. 3) Identify the source of meibocyte and ductal epithelial renewal through lineage tracing and determine the effects of environmental stress, age and sex on meibomian gland ductal epithelial and meibocyte renewal using Confetti and the H2B-GFP/K5tTA mice and IT reconstruction.