EXPRESSION OF AN FSH ANALOG WITH A REROUTED SECRETION PATTERN IN TRANSGENIC MICE

描述（由申请人提供）：人垂体激素促黄体生成素（LH）和促卵泡素（FSH）是糖蛋白异二聚体家族的一部分，由一个共同的1亚基和一个垂体特异性1亚基组成。它是决定每种激素的生物特异性的亚基。这些蛋白质的一个关键特征是它们独特的分泌模式。LH通过调节途径释放，即，它由促分泌素释放，而FSH主要是组成性分泌。这些途径对于LH和FSH在生殖中的协调作用至关重要。确定决定LH和FSH的分类和运输的决定因素一直是我实验室的主要重点。使用转染的垂体生长激素衍生的GH 3细胞，在LH亚基的羧基端的一个新的序列指导LH调节途径被确定。此外，由FSH亚基和该肽组成的嵌合体被转移到受调节的途径。该R 03试点提案的主要目的是检验这种FSH类似物可以重新路由到转基因小鼠垂体中的调节途径的假设。因此，引导FSH从正常的组成性分泌到调节途径的生理后果是什么？这些实验将采用FSH <$敲除小鼠，使用人FSH <$野生型或人FSH <$类似物转基因。该模型的优点是可以在没有内源性小鼠FSH背景的转基因小鼠中检查分选和功能。我们将研究从切除的垂体分泌和潜在的生理后果的转基因小鼠分泌FSH通过调节途径。垂体促性腺激素在体内的重新路由的能力代表了性腺功能障碍的一个潜在的重要模型，并提供了一种新的方式来检查正常的，并最终在人类生殖道的病理生理事件。 公共卫生相关性：本文提出的研究旨在研究FSH和LH分泌途径与激素功能之间的联系。从我们的工作中获得的数据将有助于理解这些激素和卵泡发育之间的相互作用。此外，性腺功能亢进或减退的病理可能归因于垂体FSH和/或LH的异常分泌。

DESCRIPTION (provided by applicant): The human pituitary hormones lutropin (LH) and follitropin (FSH) are part of a family of glycoprotein heterodimers comprised of a common 1 subunit and a hormone-specific ¿ subunit. It is the ¿ subunit that determines the biological specificity of each hormone. A critical feature of these proteins is their unique secretory patterns. LH is released through a regulated pathway, i.e., it is released by secretagogue, whereas FSH is primarily secreted constitutively. These routings are essential for the coordinated roles of LH and FSH in reproduction. Identifying the determinants that account for the sorting and trafficking of LH and FSH has been a major focus of my laboratory. Using transfected pituitary somatotrope-derived GH3 cells, a novel sequence at the carboxyl end of the LH¿ subunit directing LH to the regulated pathway was identified. Moreover, a chimera comprised of the FSH¿ subunit and this peptide was diverted to the regulated pathway. The primary objective of this R03 pilot proposal is to test the hypothesis that this FSH analog can be rerouted to the regulated pathway in pituitaries of transgenic mice. Thus, what are the physiological consequences of directing FSH from its normal constitutive secretion to the regulated pathway? These experiments will employ FSH¿ knock-out mice using either the human FSH¿ wild type or the human FSH¿ analog transgenes. The advantage of this model is that the sorting and function can be examined in transgenic mice without the background of endogenous mouse FSH. We will examine the secretion from excised pituitaries and potential physiological consequences for the transgenic mice secreting FSH through the regulated pathway. The ability to reroute the pituitary gonadotropins in vivo represents a potentially important model for gonadal dysfunction and provides a novel way to examine normal and ultimately pathophysiological events in the human reproductive tract. PUBLIC HEALTH RELEVANCE: The studies proposed here are designed to study the link between the secretion pathways of FSH and LH and hormonal function. The data obtained from our work will aid in understanding the interplay between these hormones and the development of the follicle. In addition, pathologies in which there is hyper- or hypogonadism can likely be attributed to aberrant secretion of FSH and/or LH from the pituitary.