CORTICOSTEROIDS, STRESS AND LEYDIG CELL FUNCTION

描述：（改编自申请人的摘要）Leydig细胞含有 糖皮质激素受体和响应糖皮质激素通过降低其速率 睾丸激素的分泌糖皮质激素的血清水平增加， 各种各样的条件引起的压力，包括疾病，运动和 心理社会互动根据这些事实，申请人和其他 研究人员假设男性生殖功能的下降 与压力有关的部分原因是Leydig细胞的直接抑制 糖皮质激素因此，申请人将检验以下假设： 在急性应激两小时内发生的睾丸激素下降， 不依赖于促黄体激素，并直接由糖皮质激素介导 作用于睾丸间质细胞他还将调查的生理作用， 11 β-羟基类固醇脱氢酶（11 β HSD），因为这种酶是 在Leydig细胞中大量表达并代谢糖皮质激素。三 提出了具体目标。目的（1）检测糖皮质激素的作用 通过Leydig细胞中的糖皮质激素受体（GR）介导，使用 肾上腺切除的大鼠和小鼠与间质细胞特异性敲除GR。 具体目标（2）将定义压力对Leydig细胞的影响。 目的（3）确定高剂量糖皮质激素的持续效应 暴露于应激后， 子宫内、围产期或成年期。这些研究将是第一个 确定GR介导的糖皮质激素对Leydig的直接作用程度 细胞在压力下其他应激诱导因子如一氧化氮和 将在睾丸水平监测β-内啡肽，因为它们可能影响 Leydig细胞功能独立和/或除了糖皮质激素。的 Leydig细胞中11 β HSD是应激的关键决定因素的假说 11 β氧化是一种常见的氧化模式， 成人Leydig细胞中的11 β HSD催化。反之亦然 未成熟的Leydig细胞，其中11 β-还原酶占主导地位。余额 氧化和还原催化活性显示的1型亚型的 Leydig细胞中的酶可以通过细胞内条件调节， 糖皮质激素效应的微调，受压力的影响。因此 申请人还将测试在细胞中内源性抑制剂的存在。 选择性调节11 β HSD的这些相反活性的睾丸。 预期的结果将表明，11 β HSD是一个关键的细胞内 睾丸间质细胞中睾酮生成的调节剂。

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.