GH-DEPENDENT VS -INDEPENDENT EFFECTS OF IGF-I ON PUBERTY

IGF-I 对青春期的 GH 依赖性与独立性影响

• 批准号: 6094646
• 负责人: Andrzej Bartke
• 金额: $ 7.05万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY CARBONDALE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2002-04-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6094646
• 关键词: age difference; animal puberty; brain; developmental genetics; gene expression; gene targeting; genetically modified animals; growth factor receptors; hormone receptor; hormone regulation /control mechanism; hormone sensitivity /resistance; hypothalamic pituitary axis; insulinlike growth factor; laboratory mouse; ovary; ovulation; pituitary gonadal axis; precocious puberty; protein biosynthesis; protein protein interaction; receptor expression; somatotropin; testis

Both growth hormone (GH) and the main mediator of its actions, insulin-like growth factor-I (IGF-I) can affect reproductive development and function. However, the multiple interactions between the GH-IGF-I axis and the hypothalamic-pituitary-gonadal (H-P-G) axis are poorly understood. In particular, the specific roles of direct actions of GH and IGF-I present in the systemic circulation versus the role of local IGF-I production in the control of puberty and adult reproductive functions remain to be delineated. Mice with GH resistance due to targeted disruption ("knock-out, KO) of the GH receptor gene (GH-R-KO mice) have delayed puberty and quantitative deficits in adult reproductive function, although most males and some females can reproduce. In contrast, IGF-I-KO mice with complete IGF-I deficiency have underdeveloped reproductive system and are sterile. This major difference between the effects of the disruption of the IGF-I gene and the GH-R gene implies differential role of GH dependent vs. GH-independent IGF-I production. We propose to utilize the GH-R-KO mice as a model system for identifying the role of GH-dependent IGF-I production in the control of sexual maturation, and for more clearly defining the role of GH-dependent (presumably brain and gonadal rather than hepatic) IGF-I in this process. We have already determined that administration of recombinant human IGF-I will advance the age of vaginal opening in GH-R-KO mice. In the proposed studies, we will determine whether exogenous IGF-I will advance the age of first ovulation in these GH-resistant mice, and will characterize the impact of GH resistance on the expression of IGF-I and IGF-I receptor (IGF-IR) in the brain, ovaries, and testes in pre-pubertal GH-R-KO mice. In addition, we will determine the impact of GH resistance on the time course of changes in the expression of IGF-I and IGF-IR and in the function of the H-P-G axis during spontaneous puberty and during acceleration of pubertal development by treatment with IGF-I. Results of these studies will indicate whether systemic IGF-I can influence development and function of the local IGF-I systems in the hypothalamus and in the gonads during sexual maturation.

生长激素(GH)及其作用的主要介体， 胰岛素样生长因子-I(IGF-I)可影响生殖发育和 功能。然而，GH-IGF-I轴和GH-IGF-I轴之间的多重相互作用 对下丘脑-垂体-性腺轴(H-P-G)知之甚少。在……里面 特别是，生长激素和IGF-I的直接作用在 体循环与局部IGF-I产生在控制中的作用 青春期和成年生殖功能的关系仍有待描述。小鼠带有 GH受体的靶向破坏(“敲除”，KO)导致的GH抵抗 基因(GH-R-KO小鼠)在成人中有延迟的青春期和数量缺陷 生殖功能，尽管大多数雄性和一些雌性可以繁殖。在……里面 相比之下，完全缺乏IGF-I的IGF-I-KO小鼠发育不全 生殖系统和是不育的。这两种效果之间的主要区别 IGF-I基因和GH-R基因的破坏意味着不同的作用 生长激素依赖型与生长激素非依赖型IGF-I的产生。我们建议利用 GH-R-KO小鼠作为识别GH依赖的IGF-I作用的模型系统 在性成熟的控制性生产，和更明确的定义 生长激素依赖性(可能是脑和性腺而不是肝脏)的作用 IGF-I参与了这一过程。我们已经确定了政府对 重组人IGF-I将延长GH-R-KO的阴道开放年龄 老鼠。在拟议的研究中，我们将确定外源性IGF-I是否会 将这些抗生长激素小鼠的首次排卵年龄提前，并将 生长激素抵抗对胰岛素样生长因子-I和胰岛素样生长因子-I表达的影响 青春期前生长激素受体(GH-R-KO)在脑、卵巢和睾丸中的表达 老鼠。此外，我们将确定生长激素抵抗对时间的影响 胰岛素样生长因子-I和胰岛素样生长因子-IR的表达及功能的变化 自发性青春期和青春期加速期的H-P-G轴 通过使用IGF-I治疗而发展。这些研究的结果将表明 全身性IGF-I能否影响局部的发育和功能 性成熟期间下丘脑和性腺中的IGF-I系统。