FGF Regulation of GnRH Neurons
FGF 对 GnRH 神经元的调节
基本信息
- 批准号:8127602
- 负责人:
- 金额:$ 23.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-01-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAnimalsAnosmiaAttentionAutomobile DrivingAxonBasic ScienceBirthBrainCellsComplexDataDefectDevelopmentDiseaseDominant-Negative MutationElectrophysiology (science)Embryonic DevelopmentEnsureFGF8 geneFGFR1 geneFGFR3 geneFailureFertilityFibroblast Growth FactorFibroblast Growth Factor ReceptorsGene ExpressionGenesGoalsGonadotropin Hormone Releasing HormoneGrantGrowth Factor Receptor GenesHeadHealthHormonesHumanImpairmentIn VitroIndividualKallmann SyndromeKlinefelter&aposs SyndromeLeadLigandsLightMaintenanceMammalsMethodsModelingMusMutationNatureNeuronsNeurosecretory SystemsNosePatternPhasePopulationProcessPublic HealthRegulationReproductionReproductive HealthResearchRoleSignal TransductionSignaling MoleculeSterilitySystemSystems DevelopmentTestingTransgenic MiceWorkclinically relevantfibroblast growth factor receptor 4insightloss of function mutationmembermigrationmouse modelneuron developmentoffspringpostnatalprematurepreventreceptorreproductivereproductive function
项目摘要
DESCRIPTION (provided by applicant): Gonadotropin-releasing hormone (GnRH) is a neurohomrone responsible for the activation and maintenance of reproduction. Neurons that synthesize GnRH must undergo complex maturational processes during development to become a functional system capable of supporting reproduction. Once mature, the GnRH system also needs to remain functional for an appropriate duration to ensure the propagation of offspring. Thus, one's reproductive health is critically dependent on factors that orchestrate the formation and maintenance of the GnRH system. The goal of the proposed study is to understand how a group of signaling molecules, fibroblast growth factors (FGFs), and their receptors (FGFRs) regulate the developmental maturation and postnatal functionality of the GnRH system. A number of transgenic mouse models, each lacking a distinct component of the FGF signaling system, will be used to investigate if these deficiencies result in the aberrant formation or maintenance of the GnRH system, ultimately leading to sterility. In vitro culture methods, morphological analysis, gene expression studies, electrophysiology, and whole animal manipulation will be utilized for this purpose. This research is highly relevant to public health because mutations on one of the FGFRs lead to human disorders characterized by reproductive failure. Understanding how FGFs and FGFRs regulate the GnRH system could provide important insights into the nature of GnRH system disruption in these individuals. In addition, it will reveal if mutations on other genes encoding FGFs/FGFRs are also candidates for these human disorders. PUBLIC HEALTH RELEVANCE: In all mammals including humans, the secretion of a hormone called gonadotropin- releasing hormone (GnRH) from the brain is required to initiate and maintain reproduction. A very small population of cells (about 800-3000 cells) in the brain produces GnRH. During embryogenesis, these cells first arise in the nose and then migrate to the brain where they eventually settle and assume their function. If the process of maturation (including migration and other aspects) is disturbed in these cells, the animal will lose the normal ability to secrete GnRH and suffer serious fertility problems. As such, it becomes essential to identify factors that are critical in the regulation of these cells. In the previous grant period, we identified a group of factors called fibroblast growth factors (FGFs) as important regulators that drive the maturational changes of GnRH-producing cells. Since there are 22 FGFs and 4 receptors for FGFs, we need to begin to pinpoint exactly which of these is (are) absolutely critical for the maturation of GnRH-producing cells and thus fertility. This proposal aims to investigate the roles of one FGF and two receptors for FGFs in inducing the maturation of GnRH-producing cells. In addition, we will investigate if these FGF and FGF receptors are needed to maintain the health of GnRH-producing cells as the animal ages, thereby preventing the premature termination of reproductive function. The proposed studies are of great clinical relevance since they identify candidate FGF and receptor genes whose mutations could cause reproductive anomalies in humans. Further, these studies allow us to probe, at the basic science level, the actual mechanisms induced by FGFs to stimulate the function of GnRH-producing cells. This will provide insights into what changes are required to make a functional hormone- producing cell.
性状(由申请方提供):促性腺激素释放激素(GnRH)是一种神经激素,负责激活和维持生殖。合成GnRH的神经元在发育过程中必须经历复杂的成熟过程,才能成为能够支持生殖的功能系统。一旦成熟,GnRH系统还需要在适当的时间内保持功能,以确保后代的繁殖。因此,一个人的生殖健康严重依赖于协调GnRH系统形成和维持的因素。这项研究的目的是了解一组信号分子,成纤维细胞生长因子(FGF)及其受体(FGFR)如何调节GnRH系统的发育成熟和出生后功能。许多转基因小鼠模型,每个缺乏FGF信号系统的独特组成部分,将用于研究这些缺陷是否导致GnRH系统的异常形成或维持,最终导致不育。体外培养方法、形态学分析、基因表达研究、电生理学和整体动物操作将用于此目的。这项研究与公共卫生高度相关,因为其中一种FGFRs的突变会导致以生殖失败为特征的人类疾病。了解FGFs和FGFRs如何调节GnRH系统可以为这些个体的GnRH系统破坏的性质提供重要的见解。此外,它将揭示编码FGF/FGFR的其他基因上的突变是否也是这些人类疾病的候选者。公共卫生关系:在包括人类在内的所有哺乳动物中,需要从大脑中分泌一种称为促性腺激素释放激素(GnRH)的激素来启动和维持生殖。大脑中的一个非常小的细胞群(约800-3000个细胞)产生GnRH。在胚胎发育过程中,这些细胞首先出现在鼻子中,然后迁移到大脑,最终在那里定居并承担其功能。如果这些细胞的成熟过程(包括迁移和其他方面)受到干扰,动物将失去分泌GnRH的正常能力,并遭受严重的生育问题。因此,识别在这些细胞的调节中至关重要的因素变得至关重要。在上一个资助期,我们确定了一组称为成纤维细胞生长因子(FGF)的因子,它们是驱动促性腺激素释放激素分泌细胞成熟变化的重要调节因子。由于有22种FGF和4种FGF受体,我们需要开始精确地确定哪些对GnRH产生细胞的成熟和生育力绝对重要。本研究旨在探讨一种FGF和两种FGF受体在诱导GnRH分泌细胞成熟中的作用。此外,我们将研究随着动物年龄的增长,是否需要这些成纤维细胞生长因子和成纤维细胞生长因子受体来维持促性腺激素释放激素产生细胞的健康,从而防止生殖功能过早终止。拟议的研究具有很大的临床意义,因为它们确定了候选FGF和受体基因,这些基因的突变可能导致人类生殖异常。此外,这些研究使我们能够在基础科学水平上探索FGF刺激GnRH产生细胞功能的实际机制。这将提供深入了解什么样的变化需要作出功能性激素产生细胞。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Pei-San Tsai其他文献
Pei-San Tsai的其他文献
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{{ truncateString('Pei-San Tsai', 18)}}的其他基金
Fibroblast Growth Factor Regulation of Gonadotropin-Releasing Hormone Neurons
成纤维细胞生长因子对促性腺激素释放激素神经元的调节
- 批准号:
7151469 - 财政年份:2004
- 资助金额:
$ 23.57万 - 项目类别:
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