Tear Film Lipid Compositional, Structural, Functional, Relationships, and Dry Eye

 描述(申请人提供)：仅在美国就有600多万人患有干眼症，可能被归类为房水生成缺陷(AD)和蒸发性干眼，这与眉板腺功能障碍(MGD)有关。干眼发生的两种机制都具有泪膜不稳定的共同特征，泪膜破裂时间较快，提示可能存在共同的泪膜结构异常，导致干眼的不稳定。我们的光谱研究已经确定了转铁蛋白脂质成分中可能导致转铁蛋白不稳定的几个潜在的异常，包括萜类、饱和、蛋白质和胆固醇酯。我们还用干眼识别了烃类构象异常。例如，当蜂蜜中的萜类化合物水平较低时，如MGD，Tf就不稳定，患者会出现干眼的症状和体征。当用阿奇霉素治疗恢复萜类化合物时，TF的稳定性就恢复了，患者不再有干眼的体征和症状。通过研究具有大范围转铁蛋白稳定性的样品，我们有最好的机会测试哪些部分对转铁蛋白稳定性是重要的。我们建议研究干眼症患者(AD和MGD)的样本和来自亚洲人的样本，因为他们的干眼症发病率比高加索人高80%。我们还将比较干眼的症状和体征随着治疗的改善而改善时，甘油和转铁蛋白的成分变化。将研究转铁蛋白、脂类和甲苯磺酸，因为它们的组成即使不是很明显，也是轻微的不同。我们建议使用光谱分析、拉曼光谱、红外光谱和核磁共振谱来确定组织因子的组成与泪膜稳定性的关系，在同一样品上进行体外和体内测量。我们建议在体外测量的转铁蛋白稳定性参数包括：表面压力-面积等温线、等环线、表面流变学、表面拉曼和定量布鲁斯特角显微镜，以评估在动态面积变化中的横向弹性和压缩和铺展能力。我们建议在体内测量几个参数，包括泪液渗透压、破裂时间和眨眼速度。天然差异和实验差异的转铁蛋白的脂质和蜂蜜的数量和组成(特别是萜类化合物、饱和度、蛋白质和胆固醇酯水平)，碳氢化合物构象，以及脂蛋白相互作用，将与转铁蛋白稳定性相关，使用主成分分析来确定转铁蛋白中的哪些部分是否以及哪些部分对转铁蛋白稳定性重要，最终目的是开发提高转铁蛋白稳定性的治疗方法。

 DESCRIPTION (provided by applicant): Dry eye affects over six million people in the United States alone and may be classified as aqueous production-deficient (AD) and evaporative, which is associated with meibomian gland dysfunction (MGD). Both mechanisms of development of dry eye share the common feature of instability of the tear film (TF) with rapid tear break-up time, suggesting there may be a shared structural abnormality of the TF that is responsible for the instability. Our spectroscopic studies have identified several potential abnormalities in the TF lipid composition that may contribute to TF instability including terpenoids, saturation, protein and cholesteryl esters. We also identified hydrocarbon conformational abnormalities with dry eye. For example, when terpenoid levels in meibum are low as in MGD, the TF is unstable and patients have the signs and symptoms of dry eye. When terpenoids are restored with azithromycin treatment, TF stability is restored and patients no longer have the signs and symptoms of dry eye. We have the best chance of testing which moieties are important to TF stability by studying samples with a wide range of TF stabilities. We propose to study samples from patients with dry eye (both AD and MGD) and samples from Asians because they have an 80% higher incidence of dry eye compared to Caucasians. We will also compare compositional changes in meibum and TF lipid when the signs and symptoms of dry eye are ameliorated with treatment. TF lipid and meibum will be studied since their composition is slightly if not significantly different. We propose to use spectroscopy, Raman, IR and NMR, to determine how TF composition relates to tear film stability measured in vitro and in vivo on the same sample. The TF stability parameters we propose to measure in vitro include: surface pressure-area isotherms, isocycles, surface rheology, surface Raman and quantitative Brewster angle microscopy to assess the meibum's lateral elasticity and capability of compressing and spreading during dynamic area changes. We propose to measure in vivo several parameters including tear osmolarity, break-up time and blink rate. Natural and experimental differences in TF lipid and meibum amount and composition (especially terpenoids, saturation, protein and levels of cholesteryl esters), hydrocarbon conformation, and lipid-protein interactions, will be correlated to TF stability using principle component analysis t determine if and which moieties in meibum are important to TF stability, with the ultimate goal of developing therapies to enhance TF stability.