CORTICOSTEROIDS, STRESS AND LEYDIG CELL FUNCTION

描述：(改编自申请人的摘要)间质细胞含有 糖皮质激素受体及其对糖皮质激素的反应 睾丸素的产生。血清中糖皮质激素水平在 由各种情况引起的压力，包括疾病、运动和 心理社会互动。基于这些事实，申请人和其他人 研究人员假设男性生殖功能下降 与应激有关的部分原因是间质细胞的直接抑制 用糖皮质激素治疗。因此，申请者将检验快速的假设 在急性应激两小时内出现的睾丸素下降是 不依赖于促黄体激素，由糖皮质激素直接介导 作用于间质细胞。他还将调查脑脊液的生理作用。 11β-羟基类固醇脱氢酶(11betaHSD)，因为该酶是 在间质细胞中大量表达，代谢糖皮质激素。三 提出了具体的目标。目的(1)是测试糖皮质激素的作用 由糖皮质激素受体(GR)介导的间质细胞，使用 切除肾上腺的大鼠和小鼠的间质细胞特异性GR基因被敲除。 明确的目标(2)将定义应激对间质细胞的影响。 目的(3)旨在确定高糖皮质激素的持续效应 应激对间质细胞类固醇合成的影响 子宫的，围产期的或成年期的。这些研究将是第一次 确定GR介导的糖皮质激素对Leydigi的直接作用程度 细胞在应激过程中。其他应激诱导因素，如一氧化氮和 将在睾丸水平监测β-内啡肽，因为它们可能会影响 间质细胞的功能独立于糖皮质激素和/或补充糖皮质激素。这个 假设间质细胞中11betaHSD是应激的关键决定因素 这一效应得到了以下事实的支持：11beta氧化是 11betaHSD在成人间质细胞中的催化作用。反之亦然 未成熟的间质细胞，其中11β-还原酶占主导地位。收支平衡 I型异构体所显示的氧化和还原催化活性 间质细胞中的酶可以根据细胞内的条件进行调节， 受压力影响的糖皮质激素效应的微调。因此， 申请者还将测试是否存在内源性抑制物 选择性地调节11betaHSD的这些相反活动的睾丸。 预期结果将显示11betaHSD是一种关键的细胞内 睾丸间质细胞产生睾酮的调节因子。

DESCRIPTION: (Adapted from the applicant's abstract) Leydig cells contain glucocorticoid receptors and respond to glucocorticoid by decreasing their rate of testosterone production. Serum levels of glucocorticoid are increased during stress caused by a wide variety of conditions, including disease, exercise and psychosocial interaction. Based upon these facts, the applicant and other investigators hypothesize that declines in male reproductive function associated with stress are due in part to the direct inhibition of Leydig cells by glucocorticoid. Therefore, the applicant will test the hypothesis that rapid declines in testosterone occurring within two hours of acute stress are independent of luteinizing hormone and are directly mediated by glucocorticoid acting on Leydig cells. He will also investigate the physiological role of 11beta-hydroxysteroid dehydrogenase (11betaHSD) because this enzyme is abundantly expressed in Leydig cells and metabolizes glucocorticoid. Three Specific Aims are proposed. Aim (1) is to test for effects of glucocorticoid mediated by glucocorticoid receptors (GR) in Leydig cells, using both adrenalectomized rats and mice with a Leydig-cell-specific knockout of GR. Specific Aim (2) will define the consequences of stress for the Leydig cell. Aim (3) is intended to identify sustained effects of high glucocorticoid concentrations on Leydig cell steroidogenesis after exposure to stress in utero, perinatally or during adulthood. These studies would be the first to establish the extent of direct, GR-mediated glucocorticoid action on Leydig cells during stress. Other stress-induced factors such as nitric oxide and beta-endorphin will be monitored at the testis level because they may affect Leydig cell function independently and/or in addition to glucocorticoid. The hypothesis that 11betaHSD in Leydig cells is a key determinant of stress effects is supported by the fact that 11beta oxidation is the usual mode of 11betaHSD catalysis in Leydig cells from adults. The reverse is true of immature Leydig cells where the 11beta-reductase predominates. The balance of oxidative and reductive catalytic activity displayed by the type 1 isoform of the enzyme in Leydig cells may be adjustable by intracellular conditions, fine-tuning of glucocorticoid effects, affected by stress. Therefore, the applicant will also test for the existence of endogenous inhibitors in the testis that selectively modulate these opposing activities of 11betaHSD. Anticipated results would show that 11betaHSD is a critical intracellular regulator of testosterone production in Leydig cells.