Neuroendocrine mechanisms of reproductive aging

生殖衰老的神经内分泌机制

• 批准号: 6921832
• 负责人: LOTHAR H JENNES
• 金额: $ 30.04万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921832
• 关键词: NMDA receptors; aging; biological signal transduction; estradiol; estrogen receptors; estrus; female; gene expression; genetically modified animals; glutamates; gonadotropin releasing factor; green fluorescent proteins; hypothalamus; immunocytochemistry; in situ hybridization; laboratory mouse; luteinizing hormone; microarray technology; neuroendocrine system; neurogenetics; neurohormones; neurons; polymerase chain reaction; radioimmunoassay; reproductive system

DESCRIPTION (provided by applicant): The overall goals of the proposed research are to determine the changes that occur in the brain during reproductive aging and to reveal the underlying mechanisms that cause a gradual decline in the regularity of the estrous cycle which is followed by a complete cessation of cyclicity in the middle-aged female mouse. The central hypothesis to be tested is that while circulating estradiol levels are normal or slightly elevated in the middle-aged mouse, the steroid signal does not reach the GnRH neurons which leads to a low preovulatory LH surge and to an irregular length of the estrous cycle. The present proposal focuses on the glutamatergic neurotransmitter system because it stimulates GnRH release,it is, at least in part regulated by estradiol and its activity or effectiveness is decreased in the middle-aged animal. In addition, changes in gene expression in GnRH neurons will be determined during reproductive aging. Specifically, Aim 1: will test the hypothesis that the glutamatergic system does not respond to gonadal steroids during reproductive senescence; Aim 2: will test the hypothesis that the glutamatergic innervation of GnRH neurons is altered or ineffective during reproductive senescence which leads to a reduced activation of the GnRH neurons during the steroid-induced surge; Aim 3: will identify changes in gene expression of GnRH neurons changes during reproductive aging. The proposed studies will provide comprehensive information on the changes that occur in the regulatory input to the GnRH neurons during reproductive aging and will determine which estradiol receptor mediates these changes. A detailed knowledge of these events will help to identify some of the basic mechanisms which underlie the inappropriate interactions between the brain and the ovaries and may provide clues for treatment of disorders that are caused by a central failure to maintain adequate GnRH release.

描述（由申请人提供）：拟议研究的总体目标是确定生殖衰老期间大脑中发生的变化，并揭示导致中年雌性小鼠发情周期规律性逐渐下降的潜在机制，随后是周期性完全停止。待检验的中心假设是，虽然中年小鼠的循环雌二醇水平正常或略有升高，但类固醇信号不能到达GnRH神经元，导致排卵前LH峰低和发情周期长度不规则。目前的建议集中在促性腺激素能神经递质系统，因为它刺激GnRH的释放，它是，至少部分地由雌二醇和它的活性或有效性在中年动物降低调节。此外，在生殖老化过程中，GnRH神经元基因表达的变化将被确定。具体地说， 目的1：将检验生殖衰老期间性腺激素能系统对性腺类固醇无反应的假设; 目标二：将检验以下假设：生殖衰老过程中GnRH神经元的肾上腺素能神经支配改变或无效，导致类固醇诱导的激增过程中GnRH神经元的激活减少; 目的3：探讨生殖衰老过程中GnRH神经元基因表达的变化。 拟议的研究将提供有关生殖衰老期间GnRH神经元调节输入发生变化的全面信息，并将确定哪种雌二醇受体介导这些变化。对这些事件的详细了解将有助于确定大脑和卵巢之间不适当相互作用的一些基本机制，并可能为治疗因中枢未能维持足够的GnRH释放而引起的疾病提供线索。