Exploratory Studies of Androgen Receptors in Axons

描述（由申请人提供）：雄激素对中枢和外周神经系统的功能发挥强大的作用，改变许多区域神经元的形态、功能、存活和恢复。雄激素被认为仅通过雄激素受体发挥其作用，雄激素受体传统上被认为是配体依赖性核转录因子。然而，自70年代后期以来，文献中已经有相当多的证据表明性腺类固醇激素的非转录作用，近年来呈指数增长，但受体或替代机制仍在很大程度上未知。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的轴突和树突中。这一发现指出了雄激素受体在哺乳动物皮层中具有一种新的、双核的作用模式的有趣的可能性。本申请中描述的探索性研究将提供必要的信息，以产生关于雄激素作用的这种潜在核内途径的假说。一组简单的实验将使用组织化学方法沿着与光镜、电子显微镜和共聚焦显微镜分析的组合，以：1）确定雄激素受体免疫反应性在轴突和终末中的亚细胞分布; 2）确定大脑皮质中雄激素受体免疫反应性轴突的来源;和3）确定雄激素受体在轴突中的表达是否是性分化的和生殖调节的。在广泛的精神和神经系统疾病的性别差异表明，雄激素在某些情况下是保护性的，而在其他情况下是有害的。因此，了解雄激素的作用机制可能提供一个重要的关键，了解和利用内源性和外源性雄激素配体对男性和女性的健康和患病的神经系统的细胞和全球的影响。

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.