ROLE OF PACAP IN THE MALE FETAL PITUITARY

描述（由申请人提供）：男性性成熟是一个复杂的过程，涉及下丘脑、垂体、睾丸和第二性器官及其相互关系的变化。这些成分中的任何一种发育不当都可能导致成年后的不孕症。不育影响了大约15%的夫妇，其中40%是男性因素导致的不育。因此，全面了解与男性性发育相关的事件可能有助于早期发现和预防成年期的不育症。此外，阐明调节男性生殖功能的众多因素可以促进男性避孕策略的发展。我们的实验室一直在研究垂体腺苷酸环化酶激活多肽（PACAP）在调节促性腺激素轴中的作用。我们之前已经证明PACAP能够在体外不同地调节两种垂体促性腺激素。PACAP刺激α亚基表达，稳定lh - β mRNA，抑制fsh - β mRNA表达。我们在雄胎大鼠的初步数据显示，出生时垂体PACAP显著下降，这与fsh - β表达的急剧上升是相互作用的。我们假设PACAP在垂体促性腺激素系统的发育和成熟中起重要作用。具体而言，我们建议：1)为胎儿和新生儿发育过程中垂体PACAP及其受体的动态变化提供解剖学、分子和发育证据。2)提供证据证明垂体源性PACAP在胚胎发育过程中调控促性腺激素的差异。3)利用促性腺和卵泡星细胞系证实垂体产物和内分泌激素使胎儿垂体前叶内PACAP基因高水平表达。4)通过分析PACAP- ko小鼠中PACAP缺乏对促性腺发育的影响，证实PACAP在促性腺发育中的重要作用。

DESCRIPTION (provided by applicant): Sexual maturation in the male is a complex process that involves changes in the hypothalamus, pituitary, testes, and secondary sexual organs and in their interrelationships. Improper development of any one of these components can lead to infertility in adult life. Infertility affects approximately 15% of couples, 40% of which are male factor infertility. Therefore, a complete understanding of the events associated with male sexual development may allow for early detection and possible prevention of infertility during adulthood. Furthermore, elucidation of the numerous factors that regulate male reproductive function could enhance the development of male contraceptive strategies. Our laboratory has been investigating the involvement of pituitary adenylate cyclase activating polypeptide (PACAP) in the regulation of the gonadotropin axis. We have previously demonstrated that PACAP is able to differentially regulate the two pituitary gonadotropins in vitro. PACAP has been shown to stimulate alpha subunit expression, stabilize LH-beta mRNA, and suppress FSH-beta mRNA expression. Our preliminary data in fetal male rats demonstrate a significant decline in pituitary PACAP at birth that is reciprocal to a dramatic rise in FSH-beta expression. We hypothesize that PACAP plays an important role in the development and maturation of the pituitary gonadotropin system. Specifically, we propose to 1) Provide anatomical, molecular and developmental evidence for dynamic changes in pituitary PACAP and its receptors during fetal and neonatal development. 2) Provide evidence that pituitary derived PACAP differentially regulates the gonadotropins during embryonic development. 3) Use gonadotroph and folliculostellate cell lines to demonstrate that pituitary products and endocrine hormones confer the high level of PACAP gene expression within the fetal anterior pituitary gland 4) Confirm the importance of PACAP on gonadotroph development by analyses of the affects of PACAP deficiency in PACAP-KO mice.