Hypothalamic Steroid Receptors and the Pathogenesis of PCOS

下丘脑类固醇受体与 PCOS 的发病机制

基本信息

批准号：
9044594
负责人：
Jon E Levine
金额：
$ 34.41万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9044594
关键词：
Address Adolescence Adult Amenorrhea Androgen Receptor Androgens Animal Model Animals Attenuated Cells Chronic Clinical Clinical Research Development Disease Early Intervention Endocrine Estradiol Estrogen Receptor alpha Estrogens Feedback Female Follicular cyst Frequencies Functional disorder Gene Expression Gene Silencing Gonadotropin Hormone Releasing Hormone Gonadotropins Hyperandrogenism Hypothalamic structure Investigation Luteinizing Hormone Macaca mulatta Mediating Messenger RNA Methods Modeling Monkeys Neurons Neurosecretory Systems Oligomenorrhea Ovarian Ovariectomy Pathogenesis Phenotype Physiologic pulse Physiological Polycystic Ovary Syndrome Population Primates Progesterone RNA Receptor Signaling Regimen Regulation Research Personnel Resistance Rodent Signal Pathway Steroid Receptors Steroids Structure of nucleus infundibularis hypothalami Syndrome Testing Testosterone Viral Vector Woman design in utero knock-down neurotransmission nonhuman primate prepuberty progesterone receptor A programs receptor relating to nervous system reproductive reproductive axis therapy development

项目摘要

Hyperandrogenism is a core feature of polycystic ovary syndrome (PCOS). PCOS is associated with reproductive abnormalities that include accelerated gonadotropin-releasing hormone (GnRH) release, LH excess, oligo- or amenorrhea, arrested ovarian follicular maturation, and development of follicular cysts. Clinical and animal studies have provided evidence that hyperandrogenism contributes to the manifestation of these abnormalities by inducing resistance to steroid negative feedback of pulsatile GnRH release. Little is known, however, about the neuronal mechanisms, including steroid receptors, signaling pathways, and neuronal populations, that mediate the negative feedback actions of estradiol and progesterone in the hypothalamus of female primates. Moreover, the pathogenic mechanisms by which androgens impair neuronal responsiveness to estrogen and progesterone feedback remain obscure. Project II studies will make use of viral vector-mediated gene silencing and a validated nonhuman primate model of androgen-induced reproductive PCOS phenotypes to address these major gaps in our understanding of the mechanisms that mediate the pathogenesis of PCOS. Using these methods, we will directly test the hypotheses that 1) estrogen receptor alpha (ERa) in hypothalamic arcuate nucleus (ARC) neurons mediates physiological negative feedback in the rhesus macaque, 2) androgen excess attenuates estrogen-induced-expression of progesterone receptors A and B (PR A/B) and confers resistance to negative feedback actions of estradiol and progesterone, and 3) reduced PR A/B expression in the ARC recapitulates the reproductive abnormalities of PCOS. These studies will thereby establish the normal physiological receptors and target cells that mediate steroid negative feedback in a primate, identify androgen-induced resistance to estradiol and progesterone actions as a fundamental pathological mechanism underlying PCOS-like reproductive dysfunction, and directly test the validity of the concept that hypothalamic resistance to progesterone is a determinant of reproductive abnormalities in PCOS.

超雄激素是多囊卵巢综合征（PCOS）的核心特征。 PCOS与生殖异常包括加速促性腺激素释放激素（GNRH）释放，LH 过量，寡毛或闭经，捕集的卵巢卵泡成熟以及卵泡囊肿的发展。临床和动物研究提供了证据表明超雄激素有助于表现通过抗脉冲GnRH释放的类固醇负反馈的抵抗力，这些异常。几乎没有然而，已知有关神经元机制，包括类固醇受体，信号通路和神经元种群，介导雌二醇和孕酮的负反馈作用女性灵长类动物的下丘脑。此外，雄激素损害的致病机制对雌激素和孕酮反馈的神经元反应性仍然晦涩。项目第二研究将利用病毒载体介导的基因沉默和经过验证的雄激素诱导的非人类灵长类动物模型生殖PCOS表型解决了我们对介导PCOS发病机理的机制。使用这些方法，我们将直接测试假设1）下丘脑弧形核（ARC）神经元中雌激素受体α（ERA）介导恒河猕猴中的生理负反馈，2）雄激素过量减弱雌激素诱导的表达孕酮受体A和B（PR A/B）的含义，并赋予对负面反馈动作的抵抗力雌二醇和孕酮的含量，以及3）弧形中的PR A/B表达降低了生殖 PCOS异常。这些研究将建立正常的生理受体和靶标在灵长类动物中介导类固醇负反馈的细胞，鉴定雄激素诱导的对雌二醇的抗性和孕酮作用是类似PCOS的基本病理机制功能障碍，直接测试下丘脑对孕酮的抗性的有效性 PCOS生殖异常的决定因素。