Sex, sex steroids and dry eye syndromes

描述（申请人提供）：眼前泪膜在维持眼表完整性，防止微生物攻击和保持视力方面起着至关重要的作用。反过来，泪膜功能障碍可能严重影响眼睛，导致角膜干燥、溃疡和穿孔，增加传染病的发病率，以及明显的视力损害和失明。无数人患有泪膜障碍，这被称为干眼综合征，分为两种主要类型：缺水型和蒸发型。缺水型干眼症是由于泪腺分泌的泪液减少所致。一个例子是Sj"gren's syndrome (SS)，这是一种常见的自身免疫性疾病，主要折磨女性并破坏泪腺。蒸发性干眼症通常是由睑板腺功能障碍引起的，可能是更年期、使用雌激素替代疗法和衰老期间干眼症的主要原因。这项资助申请的长期目标是测试我们的假设：(1)性类固醇在眼表和附件的生理调节以及泪膜的产生中非常重要；(2)性、性类固醇激素，特别是雄激素缺乏，是缺水和蒸发性干眼综合征发病的关键病因。实验程序包括小鼠模型、全基因组微阵列（如基因芯片）、实时pcr、细胞培养、免疫测定、2D凝胶、酶测定、组织学、图像分析和激素重建实验。我们的具体目标是：(1)确定性别和性类固醇影响正常和异常泪腺的机制；(2)揭示性别和性类固醇对睑板腺影响的机制；(3)探讨性和性类固醇在控制眼表和/或附件的边界润滑和表面活性剂蛋白中的作用。这些研究的结果将显著促进我们对性和性类固醇影响眼睛前段的过程的理解。此外，研究结果可能与眼睛健康相关，因为它们：(1)探索泪膜的调节；(2)可能导致临床治疗干眼综合征的特异性疗法的发展。

DESCRIPTION (provided by applicant): The preocular tear film plays an essential role in maintaining ocular surface integrity, protecting against microbial challenge and preserving visual acuity. Tear film dysfunction, in turn, may severely impact the eye and lead to desiccation, ulceration and perforation of the cornea, an increased incidence of infectious disease, and pronounced visual impairment and blindness. Countless people suffer from tear film disorders, which are termed dry eye syndromes and are classified into 2 major types: aqueous-deficient and evaporative. Aqueous- deficient dry eye is due to decreased tear secretion from the lacrimal gland. An example is Sj"gren's syndrome (SS), a common autoimmune disease that afflicts primarily women and destroys the lacrimal gland. Evaporative dry eye is typically caused by meibomian gland dysfunction and may be a major cause of dry eye during menopause, use of estrogen replacement therapy and aging. The long range objectives of this grant application are to test our hypotheses that: (1) sex steroids are extremely important in the physiological regulation of the ocular surface and adnexa, as well as the production of the tear film; and (2) sex, sex steroid hormones, and in particular androgen deficiency, are critical etiologic factors in the pathogenesis of both aqueous-deficient and evaporative dry eye syndromes. Experimental procedures include mouse models, whole genome microarrays (e.g. gene chips), real-time-PCR, cell cultures, immunoassays, 2D gels, enzyme assays, histology, image analysis and hormone reconstitution experiments. Our specific aims are to: (1) determine the mechanisms by which sex and sex steroids influence the normal and SS lacrimal gland; (2) unravel the processes underling the sex and sex steroid effects on the meibomian gland; and (3) explore the role of sex and sex steroids in the control of boundary lubrication and surfactant proteins at the ocular surface and/or adnexa. Results from these studies should significantly advance our understanding of the processes by which sex and sex steroids influence the anterior segment of the eye. In addition, findings may have health relatedness for the eye, because they: (1) explore the regulation of the tear film; and (2) may lead to the development of specific therapies for the clinical treatment of dry eye syndromes. PUBLIC HEALTH RELEVANCE: Dry eye syndrome is one of the leading causes of patient visits to eye care practitioners, as well as an important public health problem that has no cure. This disease afflicts over 30 million Americans, predominantly women, and significantly impacts their quality of life. We propose to determine why dry eye occurs primarily in women and to translate our research results into the development of new and unique therapeutic strategies to treat aqueous-deficient and evaporative dry eye.