FGF Regulation of GnRH Neurons

FGF 对 GnRH 神经元的调节

基本信息

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
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：
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&apos 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

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.

描述（由申请人提供）：促性腺激素释放激素（GNRH）是负责激活和维持再生产的神经hom子。合成GNRH必须在开发过程中必须经历复杂的成熟过程的神经元成为能够支持繁殖的功能系统。一旦成熟，GNRH系统还需要在适当的持续时间内保持功能，以确保后代的传播。因此，一个人的生殖健康取决于策划GNRH系统形成和维护的因素。拟议的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系统的发育成熟和产后功能。许多缺乏FGF信号系统的不同组件的转基因小鼠模型将用于研究这些缺陷是否导致GNRH系统的异常形成或维护，最终导致无菌。体外培养方法，形态分析，基因表达研究，电生理学和全动物操纵将用于此目的。这项研究与公共卫生高度相关，因为对FGFR的一种突变导致人类疾病，其特征是生殖失败。了解FGF和FGFR如何调节GNRH系统可以为这些个体中GNRH系统破坏的性质提供重要的见解。此外，它将揭示编码FGFS/FGFR的其他基因上的突变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，需要大脑中的一种称为促性腺激素释放激素（GNRH）的激素才能启动和维持繁殖。大脑中的非常小的细胞（约800-3000个细胞）会产生GNRH。在胚胎发生过程中，这些细胞首先出现在鼻子中，然后迁移到大脑最终定居并假定其功能的大脑中。如果这些细胞的成熟过程（包括迁移和其他方面）受到干扰，则该动物将失去分泌GNRH并遭受严重生育问题的正常能力。因此，必须确定在调节这些细胞中至关重要的因素。在上一个赠款期间，我们确定了一组称为成纤维细胞生长因子（FGF）的因素，是驱动产生GNRH产生细胞的成熟变化的重要调节剂。由于FGF有22个FGF和4个受体，因此我们需要开始准确指出其中哪种（）对于产生GNRH的细胞成熟至关重要至关重要。该建议旨在研究一种FGF和两个受体在诱导GNRH产生细胞成熟中的作用。此外，我们还将研究这些FGF和FGF受体是否需要作为动物年龄来维持产生GNRH的细胞的健康，从而防止生殖功能的过早终止。拟议的研究具有很大的临床相关性，因为它们鉴定了候选FGF和受体基因，它们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测FGF诱导的实际机制，以刺激刺激GNRH产生细胞的功能。这将提供有关制造功能激素 - 产生功能激素细胞所需的更改的见解。