Gender, sex steroids and dry eye syndromes

描述（由申请人提供）：眼前泪膜对眼内分泌起着关键作用。 在维持眼表完整性，防止微生物 挑战和保持视力。泪膜功能障碍，反过来， 严重影响眼睛并导致角膜上皮干燥， 角膜溃疡和穿孔，感染性角膜炎的发生率增加， 疾病，以及明显的视力障碍和失明。无数人 患有被称为干眼综合征的泪膜疾病， 分为两大类：缺水和蒸发。 缺水性干眼症是由于泪液分泌减少， 腺。一个例子是干燥综合征，一种常见的自身免疫性疾病， 主要折磨女性并破坏泪腺。蒸发过强型干眼 通常由睑板腺功能障碍引起，并且可能是 绝经期干眼症，雌激素替代疗法（HRT）的使用， 衰老这项拨款申请的长期目标是测试我们的 假设：（1）性类固醇在生理上非常重要， 调节泪腺和睑板腺，以及产生 泪膜;和（2）性别、性类固醇激素，特别是雄激素 缺乏，是两种发病机制中的关键病因因素 水分缺乏和蒸发性干眼综合征。实验程序 包括小鼠模型、DNA杂交阵列（即基因芯片）、RT-PCR 核糖核酸酶保护试验，原位北方、狭缝和南方印迹 杂交、细胞培养、免疫测定、HPLC/质谱、酶 分析，组织学，图像分析，激素重建实验，以及 作为人类的临床研究。我们的具体目标是：（1）确定 基因和蛋白质介导的性别相关的差异，和性别 正常和自身免疫性（即干燥综合征）泪腺的类固醇控制 综合征）小鼠;（2）确定参与的基因和蛋白质， 小鼠的性别相关变异和性类固醇调节 睑板腺;和（3）确定HRT使用的具体效果（雌激素， 或雌激素加孕酮），有或没有雄激素补充， 绝经后妇女的眼表。研究结果应 大大提高我们对性别和 性类固醇影响眼前节。此外，调查结果 可能与眼睛健康相关，因为他们：（1）探索 泪膜的调节;和（2）可能导致特定的发展 用于临床治疗干眼综合征的疗法。

DESCRIPTION (provided by applicant): 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, use of estrogen hormone replacement therapy (HRT) 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 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 include mouse models, DNA hybridization arrays (i.e. gene chips), RT-PCR, ribonuclease protection assays, Northern, slot 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) identify the genes and proteins that mediate the gender-related differences in, and the sex steroid control of, lacrimal glands in normal and autoimmune (i.e. Sjogren's syndrome) mice; (2) identify the genes and proteins involved in the gender-associated variations in, and the sex steroid regulation of, the mouse meibomian gland; and (3) determine the specific effects of HRT use (estrogen, or estrogen plus progesterone), with or without androgen supplementation, on the ocular surface of postmenopausal women. 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.