ROLE OF PACAP IN THE MALE FETAL PITUITARY

描述（由申请人提供）：男性的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。不孕症影响大约15%的夫妇，其中40%是男性因素不孕症。因此，完全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不育。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。我们实验室一直在研究垂体腺苷酸环化酶激活多肽（PACAP）在促性腺激素轴调节中的作用。我们以前已经证明，PACAP是能够差异调节两个垂体促性腺激素在体外。PACAP已显示刺激α亚基表达，稳定LH-β mRNA，并抑制FSH-β mRNA表达。我们的初步数据显示，雄性大鼠胎仔出生时垂体PACAP显著下降，这与FSH-β表达的急剧上升是相互的。我们推测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）提供解剖学，分子和发育证据垂体PACAP及其受体在胎儿和新生儿发育过程中的动态变化。2)提供证据表明垂体衍生的PACAP在胚胎发育期间对促性腺激素有差异调节。3)利用促性腺激素细胞系和卵泡星形细胞系证明垂体产物和内分泌激素赋予PACAP基因在胎儿垂体前叶内的高水平表达4）通过分析PACAP缺陷对PACAP-KO小鼠促性腺激素细胞发育的影响来证实PACAP的重要性。

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.