BRAIN AROMATASE AND REPRODUCTIVE FUNCTION

描述（改编自申请人摘要）：中枢神经系统 脊椎动物的中枢神经系统（CNS）含有一种酶复合物， 雄激素转化为雌激素（芳香酶）。 在老鼠和恒河猴的大脑中 猕猴芳香化酶活性（AA）分布不均匀， 集中在控制生殖行为的区域， 促性腺激素释放，以及其他大脑区域，从一些未知的 原因，例如，在杏仁核里 在雄性大鼠的许多脑区， AA是雄激素和雄激素受体依赖性的。 雄激素刺激AA 通过上调P450 AROM mRNA表达。 雄激素对AA的影响及其机制 P450 AROM mRNA在高等灵长类动物神经组织中的表达尚不清楚。 在 申请人提出在非人灵长类动物上进行实验 围绕两个特定目标（SA）构建，这些目标基于先前的工作 在实验室完成或正在进行。 第一个SA将使用 最近开发了核糖核酸酶保护测定法来测量P450 AROM 恒河猴脑中mRNA的分布、激素 调节和关系AA在不同的大脑部位，并比较 这些结果与已经发表的大鼠数据一致。恒河猴 对类固醇的负反馈作用产生抵抗力 长期阉割后的激素（Cx）。 第二个SA将研究 长期Cx对AA和雄激素受体（AR）动力学的影响， 它们各自的RNA在猴子大脑中的作用， 这种不应状态的细胞成分。 由于雌激素具有 广泛的神经营养作用，原位雌激素的形成， 与性类固醇不应状态相关的大脑可以解释一些 在衰老和某些疾病状态中发现的神经缺陷 在应用程序中。 这些实验一旦完成， 了解原位雌激素作用的重要新信息 在非人类灵长类动物大脑中的形成、分布和控制。 这 信息可以作为一个模型来形成关于角色的假设， 雌激素在人脑功能中的作用

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.