FGF Regulation of GnRH Neurons

FGF 对 GnRH 神经元的调节

• 批准号: 7576071
• 负责人: Pei-San Tsai
• 金额: $ 24.82万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7576071
• 关键词: Address; Age; Animals; Anosmia; Attention; Automobile Driving; Axon; Basic Science; Birth; Brain; Cells; Complex; Computer Systems Development; Data; Defect; Development; Disease; Dominant-Negative Mutation; Electrophysiology (science); Embryonic Development; Ensure; FGF8 gene; FGFR1 gene; FGFR3 gene; Failure; Fertility; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Genes; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Growth Factor Receptor Genes; Head; Health; Hormones; Human; Impairment; In Vitro; Individual; Kallmann Syndrome; Klinefelter' s Syndrome; Lead; Ligands; Light; Maintenance; Mammals; Methods; Modeling; Mus; Mutation; Nature; Neurons; Neurosecretory Systems; Nose; Pattern; Phase; Population; Process; Public Health; Regulation; Reproduction; Reproductive Health; Research; Role; Signal Transduction; Signaling Molecule; Sterility; System; Testing; Transgenic Mice; Work; clinically relevant; fibroblast growth factor receptor 4; insight; loss of function mutation; member; migration; mouse model; neuron development; offspring; postnatal; premature; prevent; public health relevance; receptor; reproductive; reproductive function

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.

描述（由申请人提供）：促性腺激素释放激素（GnRH）是一种负责激活和维持生殖的神经激素。合成GnRH的神经元必须在发育过程中经历复杂的成熟过程，才能成为一个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。该研究的目的是了解一组信号分子、成纤维细胞生长因子（FGFs）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信号系统的不同组成部分，将被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、电生理学和全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fgfr的突变导致以生殖衰竭为特征的人类疾病。了解FGFs和fgfr如何调节GnRH系统可以为这些个体GnRH系统中断的本质提供重要见解。此外，它将揭示编码FGFs/ fgfr的其他基因的突变是否也是这些人类疾病的候选者。公共卫生相关性：在包括人类在内的所有哺乳动物中，从大脑中分泌一种叫做促性腺激素释放激素（GnRH）的激素是启动和维持生殖所必需的。大脑中的一小部分细胞（大约800-3000个细胞）产生GnRH。在胚胎发育过程中，这些细胞首先在鼻子中产生，然后迁移到大脑，最终在那里定居并发挥其功能。如果这些细胞的成熟过程（包括迁移等方面）受到干扰，动物将失去正常分泌GnRH的能力，并出现严重的生育问题。因此，确定在这些细胞的调节中起关键作用的因素变得至关重要。在之前的资助期内，我们确定了一组称为成纤维细胞生长因子（FGFs）的因子作为驱动gnrh生成细胞成熟变化的重要调节因子。由于有22种FGFs和4种FGFs受体，我们需要开始精确地确定其中哪种对gnrh生成细胞的成熟和生殖能力至关重要。本研究旨在探讨一种FGF和两种FGF受体在诱导gnrh生成细胞成熟中的作用。此外，我们将研究随着动物年龄的增长，是否需要这些FGF和FGF受体来维持gnrh生成细胞的健康，从而防止生殖功能的过早终止。所提出的研究具有重要的临床意义，因为它们确定了候选FGF和受体基因，其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由FGFs诱导的刺激gnrh生成细胞功能的实际机制。这将使我们深入了解需要什么样的变化来制造一个功能性的激素产生细胞。