BRAIN AROMATASE AND REPRODUCTIVE FUNCTION

描述(摘自申请者的摘要)：中枢神经 脊椎动物的中枢神经系统(CNS)含有一种酶复合体，它能将 雄激素转化为雌激素(芳香酶)。在大鼠和恒河猴的脑中 猕猴芳香酶活性(AA)分布不均，为 集中在控制生殖行为和 促性腺激素的释放，以及在大脑的其他区域来自一些未知的 理性，例如，在杏仁核。在雄性大鼠的许多大脑区域， AA依赖雄激素和雄激素受体。雄激素刺激再生障碍性贫血 上调P450 arom基因的表达。雄激素对再生障碍性贫血及其代谢的影响 P450arom在高等灵长类动物神经组织中的表达尚不清楚。在……里面 申请者建议在非人类灵长类动物身上进行实验 围绕基于先前工作的两个特定目标(SA)构建 在他们的实验室里已经完成或正在进行。第一个SA将使用 新发展的核糖核酸酶保护法测定P450芳香烃 恒河猴脑内mRNA的分布及激素研究 不同脑区AA的调节及其与AA关系的比较 这些结果与已经在RAT上发表的数据一致。恒河猴 对类固醇的负反馈作用产生抵抗力 长期去势后的激素(CX)。第二个SA将研究 长期服用环磷酰胺对AA和雄激素受体(AR)动力学及 它们各自在猴子大脑中的RNA，以便理解 这种难解状态的细胞成分。因为雌激素有一种 广泛的神经营养作用，通过在原位形成雌激素 与性激素难治状态相关的大脑可能解释了一些 讨论了在衰老和某些疾病状态中发现的神经缺陷 在应用程序中。这些实验完成后，应该会提供 了解原位雌激素作用的重要新信息 非人灵长类动物大脑的形成、分布和控制。这 信息可以作为一种模型来形成关于 人类大脑功能中的雌激素。

DESCRIPTION (Adapted from applicant's abstract): The central nervous system (CNS) of vertebrates contains an enzyme complex which converts androgens to estrogens (aromatases). In brains of rats and rhesus macaques aromatase activity (AA) is distributed heterogeneously, is concentrated in areas that control reproductive behaviors and gonadotropin release, and in other brain regions from some unknown reason, e.g., in the amygdala. In many brains areas of the male rat, AA is androgen and androgen receptor dependent. Androgens stimulate AA by upregulating P450 AROM mRNA. The effects of androgens on AA and its P450 AROM mRNA in neural tissues of higher primates are not known. In this application the applicants propose experiments on nonhuman primates constructed around two Specific Aims (SA) which are based on prior work completed or ongoing in their laboratory. The first SA will use a recently developed Ribonuclease Protection Assay to measure P450 AROM MRNA in brains of rhesus macaques to study its distribution, hormonal regulation and relationship to AA in various brain parts and to compare these results with data already published in the rat. Rhesus monkeys develop a refractoriness to the negative feedback effects of steroid hormones after long-term castration (Cx). The second SA will study the effects of long-term Cx on AA, and androgen receptor (AR) dynamics and their respective RNAs in the monkey brain in order to understand the cellular components of this refractory state. Since estrogens have a wide range of neurotropic effects, in situ estrogen formation by the brain associated with sex steroid refractory states may explain some neurodeficiencies found in aging and certain diseased states discussed in the application. These experiments, when completed, should provide important new information for understanding the role of in situ estrogen formation, its distribution and control in nonhuman primate brains. This information can be used as a model to form hypotheses about the role of estrogens in human brain function.