Biochemistry and Biophysics of the Preocular Tear Film

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）-是一种广泛的多因素疾病，通过损害视力降低数百万人的生活质量，特别是老年人、妇女和生活在不利气候条件下的人。高达30%的普通人群受到DE的影响。目前尚无有效的DE治疗方法，FDA批准的治疗DE和CPB的唯一药物Restasis（R）在15%的患者中具有治疗效果，而安慰剂组为5%。这种疾病与非常薄的富含脂质和蛋白质的眼表结构（称为泪膜（TF））的变化有关。我们的项目的长期目标是：1）重新定义TF的生化组成和3-D结构，和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的发展很重要的成分。我们的基本假设是：1）TF的脂质组成比以前认为的更复杂：2）TF的结构由于非常特异的脂质/脂质和脂质/蛋白质相互作用而稳定;以及，3）TF不是完全液态的，而是具有类似液晶的，或凝胶-类似的结构，并且由富含特定类型的分子和超分子复合物的逐渐插入的层和区域组成。该项目的目标如下。目标1。通过比较MGS和AT的脂质特征，确定TF的脂质组分及其可能的来源，并识别和评估关键脂质组分在TF形成和维持中的作用，来挑战目前关于人TF主要由MGS形成的生化组成的观点。目标2.为了检验正常TF不是完全液体而是具有液晶样或凝胶样动态纳米结构的假设，所述动态纳米结构由富含特定类型的分子和超分子复合物的逐渐嵌入的层和区域组成，所述超分子复合物通过脂质、蛋白质、和其它分子，并且其结构易于由于其脂质和蛋白质组成、泪液渗透压、眼温、混合、环境因素等的改变而改变。确定与正常受试者相比，CPB患者中是否存在与DE症状和TF不稳定性周期性增加相关的人AT脂质和MGS周期性定性和定量变化。 公共卫生相关性：一般而言，干眼综合征（DE）及其主要形式之一-慢性后睑缘炎（CPB）-是一种广泛传播的病症，其通过损害数百万人的视力而严重恶化他们的生活质量。目前尚无有效的DE治疗方法，FDA批准的唯一用于治疗CPB的处方药Restasis（R）在15%的患者中具有治疗效果，而安慰剂组为5%。这种疾病与眼前泪膜（TF）中脂质和蛋白质的异常变化有关。该项目的目标是研究人类水性泪液和睑板腺分泌物的脂质组成的生化变化以及CPB中发生的TF的相应生物物理变化，以揭示其机制并开发更有效的诊断测试和治疗方法。

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.