Steroid Regulation of Ion Channels

离子通道的类固醇调节

• 批准号: 7322764
• 负责人: LESLIE P HENDERSON
• 金额: $ 35.98万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322764
• 关键词: Action Potentials; Acute; Address; Adolescence; Adolescent; Adult; Age; Aminobutyric Acid; Aminobutyric Acids; Anabolic steroids; Androgens; Animals; Anterior Hypothalamus; Antineoplastic Agents; Appearance; Athletic; Attention; Body Image; Brain; Cells; Censuses; Child; Chronic; Communities; Competence; Data; Development; Disruption; Drug usage; Estrus; Exposure to; Female; Female Adolescents; Fire - disasters; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Green Fluorescent Proteins; Health; Hormonal; Human; Ion Channel; Kinetics; Knockout Mice; Libido; Localized; Medial; Mediating; Mental Health; Methyltestosterone; Mus; Neurons; Neurosecretory Systems; Obesity; Pattern; Periodicity; Phosphorylation; Play; Post-Translational Protein Processing; Preoptic Areas; Process; Prosencephalon; Protein Kinase C; Puberty; Public Health; Recombinants; Regulation; Reproductive Behavior; Reproductive Health; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Role; School-Age Population; Self Administration; Steroids; Synapses; Teenagers; Transgenic Organisms; Woman; girls; high school; hypothalamic pituitary gonadal axis; male; malignant breast neoplasm; men; neurotransmission; patch clamp; programs; receptor; receptor expression; receptor function; reproductive; senescence; sex

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 ?-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.

描述（由申请人提供）：非法使用合成代谢雄激素类固醇（AAS）已成为越来越重要的健康问题。虽然媒体关注的关注是成年男性精英运动员的关注，但对科学和公共卫生社区中AAS的自我管理的担忧已转移到初中和高中时代和高中时代的孩子，尤其是少女对这些类固醇的日益增长的使用。这些青少年的许多用户中有许多没有参与田径运动，而是关注身体形象，并以AAS来增强其外观。 2000年美国人口普查估计，有0.5至80万的青少年滥用AAS平均年龄为15岁。在啮齿动物中，在青春期和成年人中，AAS暴露不仅可以产生降低的生殖能力，而且还可以加速生殖衰老。与青春期的AA尤其相关，青春期发作的变化与肥胖，乳腺癌，药物使用和心理健康的长期风险增加有关。此外，先前的研究表明，女性的长期滥用风险要比男性大，而青春期和青春期青少年对AAS的有害作用异常敏感，并且在青春期引起的许多AAS效应可能无法在戒烟药物使用药物时可逆。前脑神经内分泌控制区中A-氨基丁酸A型（GABAA）受体介导的神经传递在调节青春期发作和正常成人生殖行为的表达方面起着关键作用。我们已经表明，慢性AAS治疗以年龄和性别特异性的方式在这些区域中改变了GABAA受体的表达和功能。我们还表明，急性AAS给药通过变构调节迅速改变了GABAA受体功能，并且该调节取决于受体的亚基组成。在当前的提案中，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GABA能传播和神经元活性的调节中的作用，在控制下丘脑 - 甲状腺毒性 - 核酸 - 核酸 - 核纳达尔轴的激素（GNRH）神经元中的作用。我们还将评估GABAA受体的翻译后修饰如何通过AAS调节变构调节，以及这些变化是否随着年龄，性别和激素状态而变化。我们的数据将生成重要的数据，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，以及其对男性与妇女与成人与虐待它们的儿童的影响。