GENDER, SEX STEROIDS AND DRY EYE SYNDROMES

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关键作用。 泪膜功能障碍反过来可能严重影响眼睛并导致角膜上皮干燥、角膜溃疡和穿孔、感染性疾病发病率增加以及明显的视力损害和失明。 无数的人患有泪膜疾病，这被称为干眼综合征，并分为2个主要类型：水分缺乏和蒸发。 水缺乏性干眼症是由于泪腺分泌的泪液减少. 一个例子是干燥综合征，一种常见的自身免疫性疾病，主要困扰妇女和破坏泪腺。 蒸发性干眼通常由睑板腺功能障碍引起，并且可能是绝经和衰老期间干眼的主要原因。 本资助申请的长期目标是检验我们的假设：（1）雄激素在泪腺和睑板腺的生理调节以及泪膜的产生中极其重要;和（2）性别、性类固醇激素，特别是雄激素缺乏，是缺水性干眼综合征和蒸发性干眼综合征发病机制中的关键病因因素。 实验程序涉及小鼠和兔模型、差异显示技术、RT-PCR、克隆、北方和南方印迹、原位杂交、细胞培养、免疫测定、HPLC/质谱、酶测定、组织学、图像分析、激素重建实验以及人类临床研究。 我们的具体目标是：（1）确定雄激素诱导的干燥综合征小鼠模型中泪腺炎症抑制的潜在机制;（2）鉴定参与兔睑板腺雄激素控制的基因和蛋白质;（3）确定雄激素是否调节人的泪腺和睑板腺;（4）检查干燥综合征妇女中总雄激素缺乏与干眼综合征之间是否存在相关性;和（5）评估人泪腺和睑板腺是否含有性类固醇的局部合成和作用所必需的酶机制。这些研究的结果将大大促进我们对性别和性类固醇影响眼前节的过程的理解。 此外，这些发现可能与眼睛健康相关，因为它们：（1）探索泪膜的调节;（2）可能导致开发用于临床治疗干眼综合征的特定疗法。

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.