Neuroendocrine Actions of Androgens in Female Reproduction

雄激素在女性生殖中的神经内分泌作用

• 批准号: 8809606
• 负责人: PAMELA L MELLON
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8809606
• 关键词: Address; Affect; Androgen Receptor; Androgens; Anovulation; Brain; Cells; Chronic; Disease; Endocrine System Diseases; Enzymes; Estrous Cycle; Feedback; Female; Fertility; Functional disorder; Gene Expression; Genetic; Goals; Gonadal Steroid Hormones; Gonadotropins; Hormones; Hyperandrogenism; Hypothalamic structure; In Vitro; Individual; Knowledge; Location; Luteinizing Hormone; Mediating; Modeling; Molecular Genetics; Molecular Profiling; Mus; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Obesity; Ovarian; Ovulation; Phenotype; Physiologic pulse; Physiological; Physiology; Pituitary Gland; Play; Polycystic Ovary Syndrome; Progesterone; Progesterone Receptors; Receptor Signaling; Regulation; Reproduction; Reproductive Physiology; Resistance; Role; Series; Signal Transduction; System; Technology; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Woman; Work; cell type; genetic manipulation; hypothalamic pituitary ovarian axis; in vivo; innovation; kisspeptin; male; mouse model; novel; public health relevance; reproductive; reproductive function; reproductive hormone; response

 DESCRIPTION (provided by applicant): Androgen receptor signaling is crucial for normal female reproduction and hyperandrogenemia is a fundamental aspect of the reproductive disruption seen in Polycystic Ovary Syndrome (PCOS). Either lack of androgen receptor or androgen excess disrupts normal ovulation and neuroendocrine control of female reproduction, but the mechanisms for these effects are unknown. Our overall hypotheses are: 1) androgens acting in the brain and pituitary play an important role in regulating normal female fertility, and2) excess androgens, acting through androgen receptor in the hypothalamus and pituitary, are responsible for the neuroendocrine hallmarks of PCOS: high LH, low FSH, and progesterone (P4) resistance. We will test these hypotheses in a series of three independent but interrelated Aims that focus on the role of physiological androgen signaling and androgen excess in the hypothalamus and pituitary, using a combination of genetic and androgen-excess mouse models. Approaches will utilize genetic manipulation of androgen and P4 signaling in specific cell types in normal female mice and in a novel mouse model of obese PCOS. Aim 1 will focus on the brain by assessing whether androgen receptor (AR) is required specifically in neurons for normal female reproduction and for the deleterious effects of androgen excess. Using Cre-loxP technology, AR will be selectively deleted from brain neurons, and subsequently specifically from kisspeptin neurons. Females lacking AR in these neurons will be investigated for resistance to the effects of androgen excess in the new PCOS mouse model. Aim 2 will focus on the pituitary, with the hypothesis that excess androgens act directly at the gonadotrope to dysregulate LHβ and FSHβ and gonadotropin secretion in females. Female mice lacking AR selectively in the gonadotrope will be studied for altered reproductive function and gonadotropin secretion and in response to excess androgens in the PCOS mouse model. We will use primary pituitary cells in an innovative GnRH pulse system to directly test the actions of androgens on basal and GnRH-induced pulses of LH and FSH and gonadotropin gene expression. Aim 3 will test whether androgen excess interferes with P4 feedback at the hypothalamus and pituitary, as one attribute of PCOS women is impaired P4 feedback. We will determine if progesterone receptor (PR) is regulated by androgen excess in neuroendocrine tissues and whether P4 feedback is impaired by the actions of excess androgens. We will then remove PR selectively from brain neurons, kisspeptin neurons, or pituitary gonadotropes to investigate which cells mediate P4 negative feedback and the alterations caused by androgen excess. Together, these Aims will elucidate the role of AR and PR in the neuroendocrine system in normal female reproduction and illuminate the role of excess androgens in the dysregulation of neuroendocrine control of reproduction.

 描述（由应用提供）：雄激素受体信号对于正常的女性繁殖至关重要，高狂源性血症是多囊卵巢综合征（PCOS）中生殖破坏的基本方面。缺乏雄激素受体或雄激素过量会破坏女性繁殖的正常排卵和神经内分泌的控制，但是这些作用的机制尚不清楚。我们的总体假设是：1）在控制正常的女性生育方面起作用的雄激素在控制正常的女性生育方面起着重要作用，而2）超过雄激素，通过下丘脑和pitutai中的雄激素受体作用，是PCOS的神经内核值，PCOS的神经内分泌标志：高LH，LH，低FSH，低FSH和祖先（P4）（P4）。我们将在下丘脑和垂体中使用遗传学和雄激素传播小鼠模型的组合，以三个独立但相互关联的目的在一系列独立但相互关联的目标中检验这些假设。方法将利用正常雌性小鼠的特定细胞类型的雄激素和P4信号传导的遗传操纵以及新型的肥胖PCOS小鼠模型。 AIM 1将通过评估在正常女性繁殖以及超过雄激素的删除作用的神经元中是否需要专门为雄激素受体（AR）来关注大脑。使用CRE-LoxP技术，AR将从脑神经元中选择性删除，然后专门从Kisspeptin神经元中删除。这些神经元缺乏AR的女性将被研究，以使新的PCOS小鼠模型中的雄激素影响超过雄激素的影响。 AIM 2将集中在垂体上，假设超过雄激素直接作用于促性腺激素，以使女性中的LHβ和FSHβ和促性腺激素分泌失调。将研究促性腺激素缺乏AR的雌性小鼠，以改变生殖功能和促性腺激素分泌，并响应PCOS小鼠模型中过量的雄激素。我们将在创新的GNRH脉冲系统中使用原代垂体细胞直接测试雄激素对LH，FSH和FSH和GONADOTROPIN基因表达的基本和GnRH诱导的脉冲的作用。 AIM 3将测试雄激素是否超过下丘脑和垂体上P4反馈的干扰，因为PCOS女性的一个属性受到P4反馈的损害。我们将确定神经内分泌组织中的雄激素（PR）是否受雄激素的调节以及P4反馈是否受到过量雄激素的作用的损害。然后，我们将从脑神经元，Kisspeptin神经元或型促性腺促性腺激素中有选择地去除PR，以研究哪些细胞介导P4负反馈以及雄激素引起的改变。总之，这些目标将阐明AR和PR在神经内分泌系统正常女性繁殖中的作用，并阐明过量雄激素在神经内分泌控制繁殖失调中的作用。