Sex, sex steroids and dry eye syndromes

描述：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重要作用。反过来，泪膜功能障碍可能严重影响眼睛，导致角膜干燥、溃疡和穿孔，增加传染病的发病率，以及明显的视力损害和失明。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。缺水性干眼症是由于泪腺分泌的泪液减少所致。格林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。蒸发性干眼症通常是由睑板腺功能障碍引起的，可能是更年期、使用雌激素替代疗法和衰老期间干眼症的主要原因。这项资助申请的长期目标是测试我们的假设：(1)性类固醇在眼表和附件的生理调节以及泪膜的产生中非常重要；(2)性、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。实验程序包括小鼠模型，全基因组微阵列（如基因芯片），实时pcr，原位杂交，细胞培养，免疫测定，2D凝胶，MALDI/质谱，酶测定，组织学，图像分析，激素重建实验，以及使用受控环境室。我们的具体目标是：(1)鉴定在正常和/或自身免疫性（即格林综合征）小鼠中介导泪腺和睑板腺性别相关差异和性类固醇控制的基因和蛋白质；(2)检查性别和性类固醇对干眼症发展的影响；(3)确定人泪腺、睑板腺、角膜、结膜基因表达存在的性别相关差异。这些研究的结果将显著促进我们对性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。

DESCRIPTION: The preocular tear film plays an essential 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, 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 Sj¿gren'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 replacement therapy 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 ocular surface and adnexa, as well as the production of the tear film; and (2) sex, 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, whole genome microarrays (e.g. gene chips), real-time-PCR, in situ hybridization, cell cultures, immunoassays, 2D gels, MALDI/mass spectrometry, enzyme assays, histology, image analysis, hormone reconstitution experiments, as well as use of a controlled environment chamber. Our specific aims are to: (1) identify the genes and proteins that mediate the sex-related differences in, and the sex steroid control of, lacrimal and meibomian glands in normal and/or autoimmune (i.e. Sj¿gren's syndrome) mice; (2) examine the influence of sex and sex steroids on the development of dry eye; and (3) identify the sex-related differences that exist in the gene expression of the human lacrimal and meibomian glands, cornea and conjunctiva. Results from these studies should significantly advance our understanding of the processes by which sex 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.