GENDER, SEX STEROIDS AND DRY EYE SYNDROMES

眼前泪膜在维持眼表完整性、抵御微生物攻击、保持视力等方面起着至关重要的作用。反过来，泪膜功能障碍可能会严重影响眼睛，导致角膜上皮干燥、溃疡和角膜穿孔，增加感染性疾病的发生率，并显著损害视力和失明。无数的人患有泪膜紊乱，这被称为干眼综合征，分为两种主要类型：缺水和蒸发。缺水干眼是由于泪腺分泌泪液减少所致。干燥S综合征就是一个例子，这是一种常见的自身免疫性疾病，主要困扰女性，并破坏泪腺。蒸发性干眼通常是由额叶腺功能障碍引起的，可能是更年期和衰老期间干眼的主要原因。这项赠款申请的长期目标是检验我们的假设：(1)雄激素在泪腺和眉板腺的生理调节以及泪膜的产生中极其重要；(2)性别、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因素。实验程序包括小鼠和兔模型、差异显示技术、RT-PCR、克隆、Northern和Southern杂交、原位杂交、细胞培养、免疫分析、高效液相/质谱仪、酶分析、组织学、图像分析、激素重建实验以及人类的临床研究。我们的具体目标是：(1)确定雄激素诱导的干燥S综合征小鼠模型抑制泪腺炎症的机制(S)；(2)确定参与雄激素控制兔睑板腺的基因和蛋白；(3)确定雄激素是否调节人类的泪腺和眉板腺；(4)研究总雄激素缺乏与干燥S综合征患者干眼综合征之间是否存在相关性；以及(5)评估人类泪腺和眉板腺是否包含使性类固醇的局部合成和作用所需的酶机制。这项研究的结果将极大地促进我们对性别和性激素影响眼前段的过程的理解。此外，这些发现可能与眼睛的健康有关，因为它们：(1)探索泪膜的调节；(2)可能导致临床治疗干眼症的特定疗法的发展。

The preocular tear film plays a critical 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 of the corneal epithelium, 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 Sjogren s syndrome, 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 and aging. The long range objectives of this grant application are to test our hypotheses that: (1) androgens are extremely important in the physiological regulation of the lacrimal and meibomian glands, as well as the production of the tear film; and (2) gender, 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 involve mouse and rabbit models, differential display techniques, RT-PCR, cloning, Northern and Southern blots, in situ hybridization, cell cultures, immunoassays, HPLC/mass spectrometry, enzyme assays, histology, image analysis, hormone reconstitution experiments, as well as clinical studies with humans. Our specific aims are to: (1) define the mechanism(s) underlying the androgen-induced suppression of lacrimal gland inflammation in mouse models of Sjogren s syndrome; (2) identify the genes and proteins involved in the androgen control of the rabbit meibomian gland; (3) determine whether androgens regulate the lacrimal and meibomian glands of humans; (4) examine whether a correlation exists between total androgen deficiency and dry eye syndromes in women with Sjogren s syndrome; and (5) evaluate whether the human lacrimal and meibomian glands contain the enzymatic machinery necessary for the local synthesis and action of sex steroids. Results from the studies should significantly advance our understanding of the processes by which gender 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.