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Genes regulated by activin receptor II signaling in gonadotropes

促性腺激素中受激活素受体 II 信号传导调节的基因

基本信息

批准号：
7614334
负责人：
T. RAJENDRA KUMAR
金额：
$ 7.35万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-11 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7614334
关键词：
ACVR2 gene ACVR2B gene Activin Receptor Activins Affect Age Amenorrhea Applications Grants Biology Body part Candidate Disease Gene Cell Line Clinical Data Databases Defect Development Diagnosis Disease Endocrinology Exhibits Fertility Fluorescence Follicle Stimulating Hormone Gene Expression Gene Expression Profiling Gene Proteins Genes Genetic Genetic Models Glycoproteins Goals Gonadal structure Gonadotrope Cell Green Fluorescent Proteins Growth Homeostasis Hormones Hypothalamic structure In Vitro Infertility Knockout Mice Knowledge Label Lesion Mediator of activation protein Medicine Methods Molecular Mouse Strains Mus Mutant Strains Mice Ovarian Hyperstimulation Syndrome Physiology Pituitary Gland Pituitary Neoplasms Play Population Population Heterogeneity Process Production Protein-Serine-Threonine Kinases Proteins RNA Receptor Signaling Regulation Reporter Reproduction Reproductive Physiology Research Research Personnel Resources Role Sampling Signal Pathway Signal Transduction Signal Transduction Pathway Sorting - Cell Movement Syndrome Testing Time Tissues Transgenes Transgenic Mice Work autocrine base cell type design expectation improved in vitro Model in vivo innovation insight novel novel therapeutics paracrine promoter receptor reproductive reproductive axis response sex therapeutic target

项目摘要

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.

描述（由申请方提供）：激活素在性腺中大量表达，并在垂体和下丘脑内引起重要的自分泌/旁分泌作用。激活素通过两种类型的受体传递信号，激活素受体II（ACVR 2）和IIB（ACVR 2B）。ACVR 2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，ACVR 2信号传导对于垂体中FSH稳态是重要的，因为Acvr 2敲除小鼠具有抑制FSH合成和分泌的水平。尽管有这些知识，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最终调节FSH合成和分泌的激活素信号通路的体内机制。中心假设是ACVR 2信号通路下游的几个关键已知/未知基因必须在Acvr 2突变小鼠的促性腺激素细胞中受到影响。这一假设将在两个具体目标中得到检验。在具体目标1中，我们将使用一种新的转基因小鼠品系，其中促性腺激素用GFP标记。这些小鼠将与Acvr 2缺失小鼠和通过基于GFP荧光的流式分选纯化的促性腺激素细胞杂交。该方法将在期望的时间点提供从未在体内暴露于ACVR 2信号传导的纯促性腺激素群体。在特定目标2中，将使用从表达GFP转基因的对照和Acvr 2缺失小鼠分离的促性腺激素RNA样品进行微阵列分析。这些研究将为促性腺激素中激活素信号通路提供新的知识，并确定对FSH合成和分泌重要的新候选基因/蛋白质。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依赖性生育/不育疾病提供了长期的临床益处。最后，由于激活素调节整个生殖轴和身体其他部位的多个过程，因此从拟议的研究中获得的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制见解。项目叙述：这些研究应该提供关于脑垂体如何合成和分泌一种称为卵泡刺激素（FSH）的重要激素以响应另一种称为激活素的本地产生的蛋白质的新知识。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依赖性生育/不育疾病提供了临床益处。这些包括卵巢过度刺激综合征，闭经和睾丸缺陷。