Biochemistry and Biophysics of the Preocular Tear Film

眼前泪膜的生物化学和生物物理学

• 批准号: 8230756
• 负责人: Igor A Butovich
• 金额: $ 30.45万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230756
• 关键词: 3-Dimensional; Accounting; Address; Affect; Anti-Bacterial Agents; Attention; Biochemical; Biochemistry; Biophysics; Cell membrane; Chronic; Climate; Complex; Development; Diagnostic tests; Differential Scanning Calorimetry; Disease; Drops; Drug Prescriptions; Dry Eye Syndromes; Elderly woman; Environmental Risk Factor; Evaluation; Eye; FDA approved; Film; Fluorescence Microscopy; Free Energy; Gel; General Population; Goals; Human; Hydrophobic Interactions; Indium; Lead; Life; Link; Lipids; Lipoproteins; Liquid substance; Modeling; Nanostructures; Nature; Nutritional; Osmolalities; Patients; Periodicity; Pharmaceutical Preparations; Phase; Placebos; Property; Proteins; Proteomics; Publications; Quality of life; Reporting; Research; Risk; Role; Sampling; Seasons; Sodium Chloride; Source; Structure; Structure-Activity Relationship; Surface; Symptoms; Techniques; Technology; Temperature; Testing; Therapeutic Effect; Time; Ulcer; Variant; Vision; aqueous; biophysical chemistry; effective therapy; eye dryness; liquid crystal; meibomian gland; meibomian gland dysfunction; ocular surface; public health relevance; research study; sample collection; self assembly; three dimensional structure; tool; two-dimensional; viscoelasticity

DESCRIPTION (provided by applicant): Dry eye (DE), and one of its major forms - chronic posterior blepharitis (CPB) - is a widespread multifactorial disease that diminishes the quality of life of millions of people, especially elderly, women, and those who live in adverse climates, by impairing their vision. Up to 30% of the general population is affected by DE. No effective treatment for DE exists at present with the only FDA-approved drug for treating DE and CPB, Restasis(R), having a therapeutic effect in 15% of patients vs. 5% in the placebo group. The disease is linked to changes in the very thin lipid- and protein rich ocular surface structure called tear film (TF). The long-term goals of our project are: 1) to redefine the biochemical composition and 3-D structure of TF, and 2) to determine the major biochemical and biophysical factors that stabilize or destabilize TF and hence those components important for the development of CPB and DE in general. Our general hypotheses are that: 1) the lipid composition of TF is more elaborate than previously thought; 2) the TF structure is stabilized due to very specific lipid/lipid and lipid/protein interactions; and, 3) TF is not quite liquid but instead has either a liquid crystal-like, or a gel-like structure and is composed of gradually intercalating layers and zones enriched with particular types of molecules and supramolecular complexes. The aims of the project are as follows. Aim 1. To challenge the current views on the biochemical composition of human TF as formed primarily of MGS by comparatively characterizing the lipids of MGS and AT, determining the lipid components of TF and their likely sources, and identifying and evaluating the roles of the critical lipid components in the formation and maintaining of TF. Aim 2. To test the hypothesis that normal TF is not quite liquid but instead has an either liquid crystal-like or a gel- like dynamic nanostructure composed of gradually intercalating layers and zones enriched with particular types of molecules and supramolecular complexes which is stabilized by ionic and hydrophilic/hydrophobic interactions between lipids, proteins, and other molecules and whose structure is susceptible to changes due to alterations in its lipid and protein compositions, tear osmolality, ocular temperature, mixing, environmental factors, etc. Aim 3. To determine whether or not there are cyclic qualitative and quantitative changes in human AT lipids and MGS that could be associated with the cyclic increase of DE symptoms and TF instability in CPB patients compared with normal subjects. PUBLIC HEALTH RELEVANCE: Dry eye syndrome (DE) in general, and one of its major forms - chronic posterior blepharitis (CPB) - is a wide- spread condition that severely deteriorates the quality of life of millions of people by impairing their vision. No effective treatment for DE exists at present with the only FDA approved prescription drug for treating CPB, Restasis(R), having a therapeutic effect in 15% of patients vs. 5% in the placebo group. The disease is related to abnormal changes in lipids and proteins in the preocular tear film (TF). The goal of the project is to investigate the biochemical changes in lipid composition of human aqueous tears and meibomian gland secretions and the corresponding biophysical changes in TF that occur in CPB in order to uncover their mechanisms and develop more effective diagnostic tests and treatments of this condition.

描述（由申请人提供）：干眼症 (DE) 及其主要形式之一 - 慢性后睑缘炎 (CPB) - 是一种广泛存在的多因素疾病，它通过损害视力来降低数百万人的生活质量，特别是老年人、妇女和生活在恶劣气候下的人。高达 30% 的普通人群受到 DE 的影响。目前尚无针对 DE 的有效治疗方法，FDA 批准的唯一用于治疗 DE 和 CPB 的药物 Restasis(R) 对 15% 的患者有治疗效果，而安慰剂组只有 5%。该疾病与称为泪膜（TF）的非常薄的富含脂质和蛋白质的眼表结构的变化有关。我们项目的长期目标是：1) 重新定义 TF 的生化成分和 3-D 结构，2) 确定稳定或不稳定 TF 的主要生化和生物物理因素，从而确定那些对 CPB 和 DE 发展重要的成分。我们的一般假设是：1）TF 的脂质成分比之前想象的更复杂； 2) 由于非常特异性的脂质/脂质和脂质/蛋白质相互作用，TF结构得以稳定； 3) TF 并不完全是液体，而是具有液晶状或凝胶状结构，并且由逐渐插入的层和区域组成，这些层和区域富含特定类型的分子和超分子复合物。该项目的目标如下。目的 1. 通过比较 MGS 和 AT 的脂质，确定 TF 的脂质成分及其可能来源，并识别和评估关键脂质成分在 TF 形成和维持中的作用，挑战目前关于人类 TF 主要由 MGS 形成的生化成分的观点。目标 2. 检验以下假设：正常 TF 不完全是液体，而是具有液晶状或凝胶状动态纳米结构，由逐渐插入的层和区域组成，富含特定类型的分子和超分子复合物，通过脂质、蛋白质和其他分子之间的离子和亲水/疏水相互作用来稳定，其结构是敏感的 目标 3. 确定人 AT 脂质和 MGS 是否存在周期性定性和定量变化，这些变化可能与 CPB 患者与正常受试者相比 DE 症状和 TF 不稳定的周期性增加有关。 公众健康相关性：一般而言，干眼综合症 (DE) 及其主要形式之一 - 慢性后睑缘炎 (CPB) - 是一种广泛传播的疾病，会损害数百万人的视力，从而严重恶化他们的生活质量。目前，DE 尚无有效的治疗方法，FDA 批准的唯一用于治疗 CPB 的处方药 Restasis(R)，对 15% 的患者有治疗效果，而安慰剂组只有 5%。该疾病与眼前泪膜（TF）中脂质和蛋白质的异常变化有关。该项目的目标是研究体外循环中发生的人房水和睑板腺分泌物脂质成分的生化变化以及 TF 的相应生物物理变化，以揭示其机制并开发针对这种情况的更有效的诊断测试和治疗方法。