Regulation of prolactin secretion at the lactotroph

描述(申请人提供)：本申请的中心假设是，在生理条件下，垂体腺前叶的催乳素分泌受到多巴胺的抑制和催产素的刺激，这些神经元的活动受时钟基因、下丘脑高级输入和催乳素本身的调节。这将通过追求4个具体目标来实现：(1)确定在生理条件下催乳素神经元在控制催乳素分泌中的作用。为了做到这一点，在生理诱导的PRL分泌期间，大细胞和小细胞OT神经元的FOS或FRAS染色的发生率将被表征。OT的拮抗剂将用于确定生理环境下内源OT是否控制PRL的分泌。(2)确定生理条件下OT和DA神经元活动的传入控制性质。这将通过首先确定OT神经元上是否有VIP受体，然后给VIP施加反义寡核苷酸(见进展报告和初步数据)，并确定它们对OT和DA神经元活动的影响，如FOS或FRAS染色所示。(3)确定催乳素是否反馈给催产素神经元和/或它们的传入对照以调节其活动。首先，将确定OT神经元是否有PRL受体，如果有，免疫中和循环PRL或给绵羊PRL，并确定对这些神经元活动的影响。(4)探讨参与PRL分泌的神经内分泌DA神经元昼夜节律调控的分子机制。时钟基因的表达及其在SCN、ARM或PeVN中表达的神经元在恒定环境中的表型将首先被表征。然后，利用反义技术，它们的破坏将显示表达神经元的功能。这个项目与健康相关的是提出治疗与高催乳素血症和乳腺癌相关的疾病的新方法。

DESCRIPTION (provided by applicant): The central hypothesis of this application is that under physiological conditions, prolactin secretion from the anterior lobe of the pituitary gland is inhibited by dopamine and stimulated by oxytocin and that the activities of these neurons are regulated by clock genes, higher hypothalamic input and prolactin itself. This will be accomplished by pursuing 4 specific aims: (1) To characterize the role of OT neurons in control of PRL secretion under physiological conditions. To accomplish this, the incidence of FOS or FRAs staining of magnocellular and parvocellular OT neurons will be characterized during periods of physiologically induced PRL secretion. Antagonists of OT will be used to determine if endogenous OT controls PRL secretion under physiological circumstances. (2) To determine the nature of the afferent control of OT and DA neuronal activities under physiological conditions. This will be accomplished by first determining if there are VIP receptors on OT neurons and then administer antisense oligonucleotides to VIP (see Progress Report and Preliminary Data) and determine their effects on OT and DA neuronal activity as indicated by FOS or FRAs staining. (3) To determine if PRL feeds back on either OT neurons and/or their afferent controls to regulate their activities. First, it will be determined if OT neurons have PRL receptors and if so, immunoneutralize circulating PRL or administer ovine PRL and determine the effect on activity of these neurons. (4) To determine the molecular mechanisms controlling the circadian rhythm of neuroendocrine DA neurons involved in PRL secretion. The expression of clock genes and the phenotype of the neurons expressing them in the SCN, ARM or PeVN in a constant environment will first be characterized. Then, using antisense technology, their disruption will show function of the expressing neurons. The health relatedness of this project is to suggest new ways of treating diseases related to hyperprolactinemia and breast cancer.