Steroid Regulation of Ion Channels

描述（由申请人提供）：非法使用合成代谢雄激素类固醇（AAS）已成为日益突出的健康问题。虽然媒体关注的焦点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自我管理的关注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。这些青少年用户中有许多人不参与体育运动，但他们关心身体形象，并服用AAS来改善他们的外表。2000年美国人口普查估计有50万到80万青少年滥用AAS，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。在啮齿类动物中，青春期前和成年期接触AAS不仅会导致生殖能力下降，而且会加速生殖衰老。青春期开始的变化与肥胖、乳腺癌、吸毒和精神健康方面的长期风险增加有关，这与青春期使用AAS特别相关。此外，先前的研究表明，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，并且在青春期引起的许多AAS影响可能无法在停止使用药物后逆转。前脑神经内分泌控制区γ -氨基丁酸A型（GABAA）受体介导的神经传递在调节青春期发育和正常成人生殖行为的表达中起关键作用。我们已经表明，慢性AAS治疗会以年龄和性别特异性的方式改变这些区域的GABAA受体表达和功能。我们还表明，急性AAS给药通过变构调节迅速改变GABAA受体功能，这种调节取决于受体的亚基组成。在目前的提案中，我们将利用转基因和敲除小鼠来确定a和e亚基在aas介导的gaba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）神经元中神经元活性的调节中的作用。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，以了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，以及它们在滥用它们的男性与女性、成人与儿童之间的影响有何不同。

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.