GENDER, SEX STEROIDS AND DRY EYE SYNDROMES

性别、性类固醇和干眼症

• 批准号: 2757897
• 负责人: David A. Sullivan
• 金额: $ 40.36万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2757897
• 关键词: Sjogren's syndrome; androgens; autoimmunity; cytokine; gender difference; high performance liquid chromatography; hormone regulation /control mechanism; human tissue; image processing; immunologic assay /test; immunoregulation; in situ hybridization; keratoconjunctivitis sicca; laboratory mouse; laboratory rabbit; lacrimal apparatus; lacrimal disorder; mass spectrometry; molecular cloning; neuroendocrine system; northern blottings; polymerase chain reaction; secretory immune system; secretory protein; southern blotting; tissue /cell culture

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.

眼前泪膜在维持眼表完整性、防止微生物侵袭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，导致角膜上皮干燥，角膜溃疡和穿孔，增加传染病的发病率，以及明显的视力障碍和失明。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。干燥综合征就是一个例子，这是一种常见的自身免疫性疾病，主要折磨女性并破坏泪腺。蒸发性干眼通常是由睑板腺功能障碍引起的，可能是更年期和衰老期间干眼的主要原因。这项拨款申请的长期目标是验证我们的假设：(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；(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。实验程序包括小鼠和兔子模型，差异显示技术，RT-PCR，克隆，Northern和Southern blots，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，以及与人类的临床研究。我们的具体目标是：(1)明确雄激素诱导的干燥综合征小鼠泪腺炎症抑制的机制；(2)鉴定兔睑板腺雄激素调控相关基因和蛋白；(3)确定雄激素是否调节人的泪腺和睑板腺；(4)探讨干燥综合征患者总雄激素缺乏与干眼综合征的相关性；(5)评估人类泪腺和睑板腺是否含有局部合成和作用性类固醇所必需的酶机制。这些研究的结果将显著促进我们对性别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。