Gonadal Steroid Receptors and the Hypothalamo-Pituitary-Adrenal Axis

性腺类固醇受体和下丘脑-垂体-肾上腺轴

基本信息

批准号：
8013781
负责人：
Robert J Handa
金额：
$ 40.79万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013781
关键词：
3-Hydroxysteroid Dehydrogenases Address Adrenal Glands Adult Agonist Androgens Androstanes Animal Model Animals Anterior Pituitary Gland Area Binding Biological Assay Brain Brain Stem Brain region Cell Line Cell Nucleus Cells Corticosterone Corticotropin Corticotropin-Releasing Hormone Data Enzymes Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogens Exhibits FOS gene Feedback Female Future Genes Genetic Transcription Glean Glucocorticoid Receptor Glucocorticoids Glycols Goals Gonadal Steroid Hormones Health Histone Acetylation Homeostasis Hormonal Hormones Human Hypothalamic structure In Situ Hybridization Infusion procedures Knock-out Knockout Mice Ligand Binding Ligands Location Messenger RNA Metabolism Mus NCOA2 gene Nature Neurons Neuropeptides Neurosecretory Systems Output Oxidoreductase Oxytocin Oxytocin Receptor Pathway interactions Pituitary Gland Pituitary-Adrenal System Publishing Rattus Recruitment Activity Regulation Regulatory Element Reporter Reporter Genes Role Sex Characteristics Site Site-Directed Mutagenesis Stanolone Steroid Receptors Steroids Stress Testing Testosterone Transgenic Mice Vasopressins biological adaptation to stress chromatin immunoprecipitation chromatin modification interest mRNA Expression male mouse model neural circuit neurobiological mechanism novel nuclear receptor coactivator 1 oxysterol 7-alpha-hydroxylase paraventricular nucleus prevent promoter psychological stressor recombinase reproductive reproductive hormone response sex

项目摘要

DESCRIPTION (provided by applicant): The long-term goals of this project are to determine the neurobiological mechanisms that underlie the sex differences in the function of the adult hypothalamo-pituitary-adrenal (HPA) axis. In humans and animals, sex differences in HPA reactivity are well established; females exhibit a more robust activation of the HPA axis following stress than do males. Our hypothesis is that sex differences in adult hormonal stress responses are primarily the result of the opposing actions of testosterone (T) and estrogen (E) on HPA function. Activation of the HPA axis is a basic response of animals to environmental perturbations that threaten homeostasis. These responses are regulated by neurons residing in the paraventricular nucleus of the hypothalamus (PVN) that synthesize and secrete corticotropin-releasing hormone (CRH). Other PVN neuropeptides, such as vasopressin (AVP) and oxytocin (OT), modulate activity of CRH neurons at the level of the PVN as well as enhancing CRH secretogogue activity at the anterior pituitary gland. The reproductive steroids, E and T can also modulate stress responses. Circulating E enhances stress activated ACTH and CORT secretion. In contrast, T decreases the gain of the HPA axis. Published and preliminary data show that androgens can act directly on PVN neurons in the male rat through a novel pathway that involves estrogen receptor beta (ERbeta), whereas E acts predominantly through ERalpha. Thus, we hypothesize that in males, T suppresses HPA function by androgen metabolites that bind ERbeta. Clues to the neurobiological mechanisms underlying such a novel action can be gleaned from studies showing extensive colocalization of ERbeta in OT-containing cells of the PVN. Hence, in this application we address the possibility that testosterone inhibits HPA reactivity by metabolizing to a compound that binds ERbeta and regulates OT containing neurons of the PVN. Furthermore, we hypothesize that this action is distinct from that found in females where estradiol is the ligand acting through ERalpha. Five specific aims are proposed. Aim 1 will identify the location and regulation of steroid metabolizing enzymes in neurons of the PVN that allow synthesis of 32-Diol. Aim 2 will use mouse models to test the hypothesis that locally synthesized 32-Diol acts upon ERbeta neurons in the PVN to inhibit HPA reactivity. Aim 3 will determine if ERbeta containing neurons regulate HPA axis function through local release of OT or extra-PVN oxytocinergic connections with limbic nuclei. Aim 4 will test the hypothesis that 32 Diol and ERbeta functionally interact with the oxytocin promoter in a ligand dependent fashion. Aim 5 will test the hypothesis that the nature of the ligand bound to ERbeta determines the assembly of co-regulatory factors recruited to target sites on the OT promoter. PUBLIC HEALTH RELEVANCE: Sex differences exist in the hormonal response of animals to physical and psychological stressors. These sex differences arise as a result of the actions of estrogen and androgen acting upon neural circuits within the hypothalamus. In this application we will test the hypothesis that the actions of testosterone act to inhibit neuroendocrine responses to stress through metabolism to 32-Diol and subsequent binding to estrogen receptor beta found in oxytocin neurons of the hypothalamus.

描述（由申请人提供）：该项目的长期目标是确定成人下丘脑 - 垂体 - 肾上腺（HPA）轴功能的性别差异的神经生物学机制。在人类和动物中，HPA反应性的性别差异已得到很好的确定。与男性相比，雌性在应力下表现出HPA轴的强化激活。我们的假设是，成人激素应力反应的性别差异主要是睾丸激素（T）和雌激素（E）对HPA功能的相反作用的结果。 HPA轴的激活是动物对威胁稳态的环境扰动的基本反应。这些反应由位于下丘脑（PVN）的室室核中的神经元调节，该神经元合成和分泌促固醇释放激素（CRH）的神经元。其他PVN神经肽，例如加压素（AVP）和催产素（OT），可以调节CRH神经元在PVN水平上的活性，并增强垂体前垂体的CRH秘诀。生殖类固醇，E和T也可以调节应力反应。循环E增强了应力激活的ACTH和CORT分泌。相反，t减少了HPA轴的增益。已发表和初步数据表明，雄激素可以通过涉及雌激素受体β（ERBETA）的新途径直接作用于雄性大鼠的PVN神经元，而E主要通过Eralpha起作用。因此，我们假设在男性中，T抑制了结合Erbeta的雄激素代谢产物的HPA功能。可以从PVN的含OT细胞中ERBETA广泛共定位的研究中收集到这种新作用的神经生物学机制的线索。因此，在此应用中，我们解决了睾丸激素通过代谢与结合ERBETA并调节含有PVN神经元的OT的化合物来抑制HPA反应性的可能性。此外，我们假设这种作用与雌二醇是通过Eralpha作用的配体的女性中发现的作用不同。提出了五个具体目标。 AIM 1将确定允许合成32-二醇的PVN神经元中类固醇代谢酶的位置和调节。 AIM 2将使用小鼠模型来测试局部合成32-二醇对PVN中ERBETA神经元作用以抑制HPA反应性的假设。 AIM 3将确定含有神经元的ERBETA是否通过局部释放OT或PVN催产毒素能与边缘核的局部释放来调节HPA轴的功能。 AIM 4将检验以下假设：32二醇和ERBETA以配体依赖性方式与催产素启动子相互作用。 AIM 5将检验以下假设：与ERBETA结合的配体的性质决定了募集到OT启动子上靶位点的共调节因子的组装。公共卫生相关性：动物对身体和心理压力源的激素反应中存在性别差异。这些性别差异是由于雌激素和雄激素作用于下丘脑内神经回路的作用而产生的。在此应用中，我们将检验以下假设：睾丸激素的作用作用于通过代谢对32-二醇的代谢抑制胁迫的反应，并随后与下丘脑催产素神经元中发现的雌激素受体β。