Gender, sex steroids and dry eye syndromes

描述(申请人提供)：眼球前泪膜起关键作用 维护眼表完整性，保护眼睛免受微生物侵袭 挑战和保持视觉敏锐度。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，感染性疾病发生率增加 疾病，以及明显的视力障碍和失明。无数的人 患有泪膜紊乱，这被称为干眼症， 主要分为两种类型：缺水和蒸发型。 缺水干眼是由于泪液分泌减少所致 腺体。一个例子是干燥综合征，一种常见的自身免疫性疾病 主要影响女性，并破坏泪腺。蒸发性干眼 通常由眉毛腺功能障碍引起，可能是 更年期干眼，使用雌激素替代疗法(HRT)和 衰老。这项拨款申请的长远目标是测试我们的 假设：(1)性类固醇在生理上极其重要 调节泪腺和眉板腺，以及生产 泪膜；(2)性别、性类固醇激素，特别是雄激素 虚，是两者发病的关键病因因素 缺水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 核糖核酸酶保护分析，Northern、Slot和Southern原位杂交 杂交、细胞培养、免疫分析、高效液相/质谱学、酶 化验、组织学、图像分析、激素重建实验 作为对人类的临床研究。我们的具体目标是：(1)确定 调节与性别有关的性别差异的基因和蛋白质 正常和自身免疫性泪腺(即干燥综合征)的类固醇控制 综合征)小鼠；(2)确定参与 小鼠的性别相关变异和性激素调节 以及(3)确定使用激素替代疗法(雌激素， 或雌激素+黄体酮)，无论是否补充雄激素， 绝经后妇女的眼表。研究的结果应该是 极大地促进了我们对性别和 性激素会影响眼球的前段。此外，调查结果 可能与眼睛的健康有关，因为他们：(1)探索 泪膜的调节；和(2)可能导致特定的 干眼症的临床治疗方法。

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.