Steroid Regulation of Ion Channels

描述(由申请人提供)：非法使用合成代谢类固醇(AAS)已成为日益突出的健康问题。虽然媒体的注意力一直集中在成年男性精英运动员身上，但科学界和公共卫生界对AAS自我管理的担忧已经转移到初中和高中年龄的儿童，特别是十几岁的女孩越来越多地使用这些类固醇。这些青少年用户中的许多人并不参与体育运动，但关心身体形象，并使用AAS来改善自己的外貌。2000年美国人口普查估计，有50万至80万青少年滥用雄激素，平均年龄为15岁。在人类中，早期暴露于高水平的雄激素会改变青春期的开始、生殖能力和性欲。在啮齿动物中，无论是在青春期之前还是在成年后，接触AAS不仅会导致生殖能力下降，还会加速生殖衰老。与青春期使用AAS特别相关的是，青春期发作的变化与肥胖、乳腺癌、药物使用和心理健康方面的长期风险增加有关。此外，以前的研究表明，滥用AAS的长期风险在女性中比在男性中更大，青春期前和青春期青少年对AAS的有害影响异常敏感，而且在青春期引发的许多AAS效应可能不会随着停止使用药物而逆转。前脑神经内分泌控制区的GABAA受体介导的神经传递在调节青春期开始和正常成人生殖行为的表达中起着关键作用。我们已经证明，慢性AAS治疗以年龄和性别特异性的方式改变这些区域的GABAA受体的表达和功能。我们还表明，急性给予AAS通过变构调节迅速改变GABAA受体的功能，这种调节依赖于受体的亚基组成。在目前的方案中，我们将利用转基因和基因敲除小鼠来确定a和e亚基在AAS介导的GABAA能传递和控制下丘脑-垂体-性腺轴的促性腺激素释放激素(GnRH)神经元活动中的作用。我们还将评估GABAA受体的翻译后修饰如何调节AAS的变构调节，以及这些变化是否随动物的年龄、性别和激素状态而变化。我们的数据将产生重要的数据，有助于理解这些类固醇如何改变神经元功能，从而对生殖健康产生影响，以及它们在男性与女性以及成年人与儿童中的影响有何不同。

DESCRIPTION (provided by applicant): Illicit use of anabolic androgenic steroids (AAS) has become an increasingly prominent health concern. While the spotlight of media attention has been on adult male elite athletes, concern over AAS self-administration in the scientific and public health communities has shifted to the growing use of these steroids by junior high- and high school-age children, especially teenage girls. Many of these adolescent users are not involved in athletics, but are concerned with body image and take the AAS to enhance their physical appearance. The 2000 US Census estimates that 0.5 to 0.8 million teenagers abuse AAS with a mean age for initiation of 15. In humans, early exposure to high levels of androgens alters the onset of puberty, reproductive competence and sexual libido. In rodents, AAS exposure, both prior to puberty and in adults, can produce not only diminished reproductive competence, but also accelerated reproductive senescence. It is particularly relevant to AAS use in adolescence that changes in pubertal onset are associated with increased long-term risks with respect to obesity, breast cancer, drug use and mental health. Moreover, previous studies suggest that long-term risks from AAS abuse are greater in women than in men, that prepubertal and pubertal adolescents are unusually sensitive to the deleterious effects of the AAS, and that many of the AAS effects elicited during adolescence may not be reversible with cessation of drug use. Neurotransmission mediated by gamma-aminobutyric acid type A (GABAA) receptors in forebrain neuroendocrine control regions plays a critical role in regulating both pubertal onset and the expression of normal adult reproductive behaviors. We have shown that chronic AAS treatment alters GABAA receptor expression and function in these regions in an age- and sex-specific manner. We have also shown that acute AAS administration rapidly alters GABAA receptor function via allosteric modulation and that this modulation depends upon subunit composition of the receptor. In the current proposal, we will take advantage of transgenic and knockout mice to determine the role of a and e subunits in AAS-mediated modulation of GABAergic transmission and neuronal activity in gonadotropin releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis. We will also assess how posttranslational modifications of the GABAA receptor regulate allosteric modulation by the AAS and if these changes vary with age, sex and hormonal state of the animal. Our data will generate data important for understanding how these steroids alter neuronal function to produce effects on reproductive health and how their effects differ in men vs. women and adults vs. children who abuse them.