SEX HORMONE REGULATION OF LACRIMAL GLAND SECRETION

描述(摘自申请者的摘要)：干眼症是 最常见的眼部疾病类别，以及 泪腺液体产生不足是导致泪液分泌不足的常见原因。 有问题。泪道功能不全大多数是由自身免疫性疾病引起的 值得注意的是干燥综合征，以及其他鲜为人知的病因。 大多数干眼症患者和绝大多数干燥综合征患者 患者，都是绝经后的女性。此外，许多女性 怀孕或正在服用口服避孕药的人不能戴隐形眼镜 晶状体由于房水泪液产量减少所致。因此，看起来 生殖激素调节泪液分泌功能 易患自身免疫性疾病。这项研究的目标是 确定调节细胞分泌状态的激素因素 女性泪腺。具体目的是检验三个假说 关于雄激素、雌激素和催乳素之间的相互作用：1. 雄激素减少和雌激素水平升高会导致泪水 不够用。因为雄激素和雌激素在 更年期，因为雌激素水平的增加会减少游离雄激素 通过增加性激素结合球蛋白的合成，这一假说 可以解释泪液功能受损的观察 绝经后和高雌激素状态。2.催乳素处于最佳状态 水平与雄激素和雌激素协同作用维持 泪腺功能正常，但不足或过多 催乳素会损害功能。3.泪腺中催乳素的合成 被雄激素和循环催乳素降低，并通过 雌激素。这一假设，将用前两种材料进行检验 特定的目标，是因为催乳素有可能 可能起到内分泌的作用，或者如果释放到间质中， 泪腺上皮细胞或淋巴细胞的自分泌或旁分泌介质 活动。兔子将被摘除卵巢，然后用雄激素治疗， 在有和没有雌激素的情况下，来检验第一个假设。他们将会是 用溴隐亭、催乳素和性激素治疗来检测第二种。 膜相关的总Na，K-ATPase，M受体和 β-肾上腺素能受体将在最初的调查中进行测量。这个 这些参数的亚细胞组织，加上Na/H反端口，将是 在最终实验中确定，将休息和胆碱 刺激泪腺流率，泪液免疫组织病理学， 和腺泡形态。催乳素mRNA丰度和免疫反应性将 被测量以检验第三个假设。如果具体的假设是 证明是正确的，实验结果应该会启发设计 预防或逆转激素介导的泪道损伤的策略 不够用。

DESCRIPTION (adapted from applicant's abstract): Dry eye disease is one of the most frequently encountered categories of ocular morbidity, and insufficient lacrimal gland fluid production is a frequent source of the problem. Lacrimal insufficiency results from autoimmune disease, most notably Sjogren's syndrome, and from other, poorly-understood etiologies. Most dry eye patients, and the vast majority of Sjogren's syndrome patients, are postmenopausal women. Additionally, many women who are pregnant or are taking oral contraceptives are unable to wear contact lenses due to decreased aqueous tear production. Thus, it appears that reproductive hormones modulate lacrimal secretory function and susceptibility to autoimmune disease. The goal of this study is to determine the hormonal factors regulating the secretory status of the female lacrimal gland. The specific aims are to test three hypotheses concerning interactions between androgens, estrogens, and prolactin: 1. Decreasing androgen and increasing estrogen levels result in lacrimal insufficiency. Because androgens as well as estrogens are lost after menopause, and because increasing estrogen levels decrease free androgens by increasing synthesis of sex hormone binding globulin, this hypothesis can account for the observation that lacrimal function is impaired both post-menopausally and in high-estrogen states. 2. Prolactin at optimal levels acts synergistically with androgens and estrogens in maintaining normal lacrimal gland function, while either insufficient or excess prolactin impairs function. 3. Prolactin synthesis in the lacrimal gland is decreased by androgens and circulating prolactin, and it is increased by estrogens. This hypothesis, to be tested with materials from the first two specific aims, is of interest because of the possibility that prolactin might act as an intracrine, or if released into the interstitium, an autocrine or paracrine mediator of lacrimal epithelial or lymphocytic activity. Rabbits will be ovariectomized, then treated with androgens, with and without estrogens, to test the first hypothesis. They will be treated with bromocriptine, prolactin, and sex steroids to test the second. Total membrane-associated Na,K-ATPase, muscarinic receptors, and beta-adrenergic receptors will be measured in initial surveys. The subcellular organization of these parameters, plus Na/H antiport, will be determined in final experiments, as will resting and cholinergically stimulated lacrimal gland fluid flow rates, lacrimal immunohistopathology, and acinar morphology. Prolactin mRNA abundance and immunoreactivity will be measured to test the third hypothesis. If the specific hypotheses are proven correct, the experimental results should inspire design of strategies for preventing or reversing hormonally-mediated lacrimal insufficiency.