Genes regulated by activin receptor II signaling in gonadotropes

描述(申请人提供)：激活素在性腺中大量表达，并在垂体和下丘脑中引发重要的自分泌/旁分泌活动。激活素通过两种受体，激活素受体II(ACVR2)和激活素受体IIB(ACVR2B)传递信号。ACVR2在进化上高度保守，是垂体促性腺激素的主要形式。我们的遗传学研究表明，由于Acvr2基因缺失的小鼠抑制了FSH的合成和分泌水平，ACVR2信号对垂体中FSH的动态平衡非常重要。尽管有这些知识，但生殖轴中的许多激活素反应基因仍然未知。我们的长期研究目标是阐明激活素信号通路在体内最终调节FSH合成和分泌的机制。中心假设是ACVR2信号通路下游的几个关键的已知/未知基因在Acvr2突变小鼠的促性腺激素中肯定受到影响。这一假设将在两个具体目标上得到检验。在特定的目标1中，我们将使用一种新的转基因小鼠品系，其中的促性腺激素被GFP标记。这些小鼠将与Acvr2基因缺失的小鼠杂交，并通过基于GFP荧光的流动分选纯化促性腺激素。这种方法将在所需的时间点提供从未在体内接触过ACVR2信号的纯促性腺激素群体。在特定目标2中，将使用从对照组和表达GFP转基因的Acvr2基因缺失小鼠分离的促性腺激素RNA样本进行微阵列分析。这些研究将提供有关促性腺激素激活素信号通路的新知识，并确定对FSH合成和分泌重要的新候选基因/蛋白。FSH产生机制的描述是生殖生理学的基础，并为诊断和治疗FSH依赖型生育/不育疾病提供长期的临床益处。最后，由于激活素调节整个生殖轴和身体其他部分的多个过程，拟议的研究结果也应该为其他组织中激活素调节的信号通路提供新的机械性见解。 项目简介：这些研究应该提供关于脑下垂体如何合成和分泌一种名为卵泡刺激素(FSH)的重要激素的新知识，以回应另一种本地生产的蛋白质激活素。FSH产生机制的描述是生殖生理学的基础，并为诊断和治疗FSH依赖型生育/不育疾病提供临床益处。这些疾病包括卵巢过度刺激综合征、闭经和睾丸缺陷。

DESCRIPTION (provided by applicant): Activins are abundantly expressed in gonads and elicit important autocrine/paracrine actions within the pituitary and hypothalamus. Activins signal through two types of receptors, activin receptor II (ACVR2) and IIB (ACVR2B). ACVR2 is highly conserved evolutionarily and is the predominant form in pituitary gonadotropes. Our genetic studies demonstrated that ACVR2 signaling is important for FSH homeostasis in pituitary, since Acvr2 null mice have suppressed levels of FSH synthesis and secretion. Despite this knowledge, many activin-responsive genes in the reproductive axis remain unknown. Our long-term research goal is to elucidate the in vivo mechanisms of activin signaling pathways that ultimately regulate FSH synthesis and secretion. The central hypothesis is that several critical known/unknown genes downstream of the ACVR2 signaling pathway must be affected in gonadotropes of Acvr2 mutant mice. This hypothesis will be tested in two Specific Aims. In Specific Aim 1, we will use a novel transgenic mouse strain, in which the gonadotropes are labeled with GFP. These mice will be intercrossed to Acvr2 null mice and gonadotropes purified by flow sorting based on GFP fluorescence. This approach will provide pure populations of gonadotropes that have never been exposed to ACVR2 signaling in vivo, at desired time points. In Specific Aim 2, microarray analyses will be performed using gonadotrope RNA samples isolated from control and Acvr2 null mice that express the GFP transgene. These studies should provide new knowledge on activin signaling pathways in gonadotropes and identify novel candidate genes/proteins that are important for FSH synthesis and secretion. Delineation of mechanisms of FSH production is fundamental to physiology of reproduction and offers long-term clinical benefits of diagnosing and treating FSH-dependent fertility/infertility disorders. Finally, because activins regulate multiple processes throughout the reproductive axis and other parts of the body, results obtained from the proposed studies should also provide new mechanistic insights into activin-regulated signaling pathways in other tissues. PROJECT NARRATIVE: These studies should provide new knowledge on how pituitary gland synthesizes and secretes an important hormone called follicle-stimulating hormone (FSH) in response to another locally produced protein called activin. Delineation of mechanisms of FSH production is fundamental to physiology of reproduction and offers clinical benefits of diagnosing and treating FSH-dependent fertility/infertility disorders. These include ovarian hyperstimulation syndrome, amenorrhea and testicular defects.