Exploratory Studies of Androgen Receptors in Axons

轴突雄激素受体的探索性研究

• 批准号: 7037595
• 负责人: Lydia L DonCarlos
• 金额: $ 16.19万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037595
• 关键词: androgen receptor; axon; cerebral cortex; confocal scanning microscopy; gender difference; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; neuronal transport; protein localization; receptor expression; testosterone; transmission electron microscopy

DESCRIPTION (provided by applicant): Androgens exert powerful effects on the function of the central and peripheral nervous system, modifying the morphology, function, survival and recovery of neurons in many regions. Androgens have been thought to exert their effects exclusively through the androgen receptor, traditionally considered to be a ligand dependent nuclear transcription factor. However, considerable evidence for non-transcriptional effects of gonadal steroid hormones has been in the literature since the late 70's and has accumulated exponentially in recent years, yet the receptors or alternative mechanisms remain largely unknown. This laboratory recently discovered that androgen receptors are present not only in neuronal nuclei, but in axons and dendrites in the mammalian cerebral cortex. This discovery points to the intriguing possibility that androgen receptors have a novel, extranuclear mode of action in the mammalian cortex. The exploratory studies described in this application will provide information essential to generating hypotheses about this potential extranuclear route of androgen action. A straightforward set of experiments will use combinations of histochemical methods along with light microscopic, electron microscopic and confocal microscopic analysis to: 1) Identify the subcellular distribution of androgen receptor immunoreactivity in axons and terminals; 2) Identify the source of androgen receptor immunoreactive axons in the cerebral cortex; and 3) Determine whether the expression of androgen receptors in axons is sexually differentiated and hormonally regulated. Sex differences in a broad range of mental and neurological disorders suggest that androgens are in some cases protective and in others deleterious. Thus, understanding the mechanisms of action of androgens may provide an essential key to understanding and exploiting the cellular and global impact of endogenous and exogenous androgenic ligands on the healthy and diseased nervous system in both men and women.

描述（由申请人提供）：雄激素对中央和周围神经系统的功能产生了强大的影响，从而改变了许多地区神经元的形态，功能，生存和恢复。人们认为，雄激素可以通过雄激素受体独家发挥作用，传统上被认为是依赖配体的核转录因子。然而，自70年代后期以来，文献中一直存在性腺类固醇激素的非转录作用的大量证据，并且近年来已经成倍地积累，但是受体或替代机制仍然在很大程度上未知。该实验室最近发现，雄激素受体不仅存在于神经元核中，而且存在于哺乳动物大脑皮层中的轴突和树突中。这一发现表明，雄激素受体在哺乳动物皮质中具有新颖的，核外的作用方式。本应用中描述的探索性研究将为产生有关这种潜在的雄激素作用外途径的假设提供必不可少的信息。一组直接的实验将使用组织化学方法的组合以及光显微镜，电子显微镜和共聚焦显微镜分析到：1）确定轴突和末端中雄激素受体免疫反应性的亚细胞分布； 2）确定大脑皮层中雄激素受体免疫反应性轴突的来源； 3）确定轴突中雄激素受体的表达是否是性别分化和荷尔蒙调节的。在广泛的心理和神经系统疾病中的性别差异表明，雄激素在某些情况下是保护性的，而在其他情况下则有害。因此，了解雄激素的作用机制可能是理解和利用内源性和外源性雄激素配体对男性和女性健康和疾病神经系统的细胞和全球影响的重要关键。