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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：
7760577
负责人：
Robert J Handa
金额：
$ 40.94万
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/7760577
关键词：
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 Histone Acetylation Homeostasis Hormonal Hormones Human Hydroxysteroid Dehydrogenases 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 Son 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 public health relevance 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.

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