Hypothalamic Control of Puberty

描述（由申请人提供）：了解青春期的机制是极其重要的，因为这个发育阶段深刻地影响着成年生活中的健康和疾病。青春期类固醇激素的增加改变了青少年行为所必需的脑回路的形成。此外，生殖障碍，包括性早熟和青春期延迟以及多囊卵巢综合征，以及精神障碍，如躁狂抑郁症和精神分裂症，都起源于这一发育阶段。父母资助的总体目标是调查下丘脑在控制青春期开始的作用。在HD11355支持的30年研究过程中，PI注意到，在WNPRC群体中，存在体重增加和月经初潮年龄下降的长期趋势。这一趋势可归因于WNPRC喂养计划的变化，并且与最近人类肥胖和月经初潮加速的长期趋势惊人地相似。由于青春期的时间与体重变化密切相关，在本研究中，我们将研究雌性恒河猴青春期开始和青春期体重增加的机制之间可能的表观遗传相互作用，作为人类的模型。要验证的假设是，过量的食物摄入会导致黄体生成素释放激素（LHRH）和/或KiSS-1基因的DNA甲基化状态降低，从而触发灵长类动物青春期的开始。这项研究的结果不仅为人类肥胖研究提供了一个非人类灵长类动物的模型，也为灵长类动物青春期发生的机制提供了新的见解，同时也为我们留住了一名具有分子生物学相关技能的工作人员。此外，本研究的结果将为WNPRC群体的卫生/饲养以及所有其他nprc和非人灵长类动物研究中心类项目提供相关信息。

DESCRIPTION (provided by applicant): Understanding the mechanism of puberty is extremely important, as this developmental stage profoundly influences health and disease in adult life. The pubertal increase in steroid hormones modifies brain circuitry formation necessary for adolescent behaviors. Moreover, reproductive disorders, including precocious and delayed puberty and polycystic ovarian syndrome, and psychiatric disorders, such as manic-depression and schizophrenia, originate at this developmental stage. The overall objective of the parent grant is to investigate the role of the hypothalamus in the control of the onset of puberty. Over the course of 3 decades of studies supported by HD11355, the PI has noticed that there is a secular trend towards heavier bodyweight and younger ages of menarche in WNPRC colony monkeys. This trend is attributable to changes in the feeding program in the WNPRC and is strikingly similar to a recent secular trend towards obesity and accelerated age of menarche in human populations. Because the timing of puberty is closely associated with bodyweight changes, in this proposed study we will examine the possible epigenetic interaction between the mechanism of the onset of puberty and pubertal bodyweight increase in female rhesus monkeys, as a model for humans. The hypothesis to be tested is that a decrease in DNA methylation status of the luteinizing hormone-releasing hormone (LHRH) and/or KiSS-1 gene by excessive food intake triggers the onset of puberty in primates. Results from this study will not only provide a non-human primate model for obesity studies in humans and new insight into the mechanism of the onset of puberty in primates, but also enable us to retain a staff member who has relevant skills in molecular biology. In addition, the results from this study will provide information relevant to the health/husbandry of the WNPRC colony as well as all other NPRCs and center-like programs in non-human primate research. PUBLIC HEALTH RELEVANCE: Studying the mechanism of puberty is very important, as disorders associated with precocious and delayed puberty, and diseases such as polycystic ovarian syndrome, anorexia nervosa, manic- depression, and schizophrenia originate at or worsen with puberty. Because the proposed study addresses the underlying mechanism of bodyweight increase and puberty, the results will significantly impact our understanding of the current trend towards obesity and early puberty onset in our human society.