NEUROENDOCRINE GENES GOVERNING REPRODUCTION

男性的生殖是由连接大脑和睾丸的荷尔蒙交流控制的。大脑整合了来自环境的线索和来自睾丸的激素信号，以调控前脑和下丘脑神经元的促性腺激素释放激素(GnRH)的分泌。GnRH指导促性腺激素、促黄体生成素和卵泡刺激素的合成和释放，而促性腺激素对睾丸功能起着控制作用。然后，睾丸中的睾丸素作用于大脑，提供调节性分化、促性腺激素分泌、性别认同和性欲的主要信号。雄激素，包括睾酮和相关化合物，正被用于男性避孕以及治疗青春期延迟，使用将继续增长--以及对其对大脑作用的更准确信息的需求。这项研究的主要目的是发现雄性猕猴前脑中睾酮作用的分子和细胞基础。雄性猕猴是一种灵长类动物，其生殖生理与人类非常相似。这个项目的具体目的是更多地了解4种特定的神经肽和苯丙胺调节转录本(CART)、刺鼠相关蛋白(AgRP)、黑色素浓缩激素(MCH)和甘丙素样肽(GALP)在控制促性腺激素分泌中的作用，以及作为睾酮和其他相关雄激素对大脑作用的分子靶点。利用系统、细胞和分子生物学技术，我们将研究这些神经肽对促黄体生成素分泌的影响，检验编码这些神经肽的基因是雄激素调节靶点的假设，确定涉及信号转导的机制，并开始绘制将这些特定分子连接到GnRH神经元的突触电路。灵长类动物的生殖生理与人类相似，了解雄激素在大脑中的细胞和分子作用，是实现将雄激素化合物投入使用的第一步，这种化合物具有最大的治疗效益，同时最大限度地减少有害副作用。随着时间的推移，这些研究提供的知识将有助于制定改进的战略，以解决人口过剩问题，增加计划生育的选择，并治疗男性生殖障碍。

Reproduction in males is governed by hormonal communication linking the brain and the testis. The brain integrates cues from the environment and hormonal signals from the testis to govern the secretion of gonadotropin-releasing hormone (GnRH) from neurons in the forebrain and hypothalamus. GnRH directs the synthesis and release of the gonadotropins, LH and FSH, which exert control over testicular function.. Testosterone from the testis then acts on the brain to provide the primary signal to regulate sexual differentiation, gonadotropin secretion, gender identity, and libido. Androgens, including testosterone and related compounds, are being used for male contraception, as well as the treatment of delayed puberty, use will continue to growth-as well the demand for more accurate information about their actions on the brain. The primary objective of this research is to discover the molecular and cellular basis of testosterone's action in the forebrain of the male macaque, a primate whose reproductive physiology closely resembles that of man. The specific aims of this project are focused on learning more about the role of 4 particular neuropeptides and amphetamine- regulated transcript (CART), agouti-related protein (AgRP), melanin- concentrating hormone (MCH), and galanin-like peptide (GALP) in the control of gonadotropin secretion and as molecular targets for the action of testosterone and other related androgens on the brain. Using systems, cellular, and molecular biological techniques, we will examine the effects of these neuropeptides on LH secretion, test the hypothesis that the genes coding for the peptides are targets for androgen regulation, identify the mechanisms involved in signal transduction, and begin to map the synaptic circuitry linking these particular molecules to GnRH neurons. Understanding the cellular and molecular actions of androgens in the brain of a primate, whose reproductive physiology is similar to humans, is the first step toward the goal of putting androgenic compounds into use that have maximum therapeutic benefits with minimal deleterious side effects. Over time, the knowledge provided by these studies will be an aide to the development of improved strategies for addressing the problems of over-population, increasing option for family planning, and treating disorders of reproduction in men.