Physiologic Role of the Somatotroph IGF-1 Receptor

生长激素 IGF-1 受体的生理作用

• 批准号: 7648027
• 负责人: Christopher Joseph Romero
• 金额: $ 5.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648027
• 关键词: Animals; Anterior Pituitary Gland; Cells; Child; Documentation; Equilibrium; Evaluation; Feedback; Figs - dietary; Future; Gene Expression; Gene Targeting; Genetic Transcription; Genotype; Goals; Growth; Growth Disorders; Growth and Development function; Guidelines; Hormonal Change; Hormone Receptor; Hormones; Human; Hypothalamic Hormones; Hypothalamic Releasing Factor; Hypothalamic structure; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Knock-out; Knockout Mice; Measurement; Mediating; Medical; Messenger RNA; Molecular; Mus; Neurosecretory Systems; Partner in relationship; Physiological; Pituitary Gland; Play; Production; Public Health; Quantitative Reverse Transcriptase PCR; Regulation; Relative (related person); Role; Sermorelin; Site; Somatostatin; Somatotropin; Stimulus; System; Testing; Transgenes; base; design; immunocytochemistry; in vivo; insight; knockout animal; recombinase

DESCRIPTION (provided by applicant): The growth hormone-insulin-like growth factor-1 (GH-IGF-1) axis plays a key role in the control of human growth and alterations in this axis usually result in growth retardation. GH synthesis and secretion by the anterior pituitary somatotrophs is under the control of stimulatory GH releasing hormone (GHRH) and inhibitory somatostatin (SST) from the hypothalamus. Many of the actions of GH are mediated by the stimulation of production of IGF-1. Although IGF-1 has been shown to have negative feedback effects on the somatotroph cell, the exact physiologic mechanism of GH regulation is unknown. In order to increase our understanding of the central feedback role of IGF-1 on somatotroph regulation, the goal of this proposal is to create a knockout mouse that lacks the IGF-1 receptor (IGF-1 R) on the somatotroph. Specific Aim #1 will involve creating the knockout animal using the cre/lox system; animals that contain loxP sites at the IGF-1 R locus will be mated with mice bearing the rGHpCre recombinase transgene. Careful documentation of the genotype and confirmation of effective recombinase activity (immunocytochemistry for GH and IGF-1 R), along with auxiologic parameters documenting growth and development as well as measurements of hormone levels will be performed with the somatotroph-specific IGF-1 receptor knockout (SIRK) and control mice. Specific Aim #2 is designed to provide evidence of the neuroendocrine role of IGF-1 feedback using provocative testing for the release of hypothalamic factors, human growth hormone releasing hormone (GHRH) and somatostatin. In addition, in order to gain some insight into the molecular mechanisms involved in negative feedback of IGF-1, quantitative reverse-transcriptase PCR will be performed to determine mRNA levels of IGF-1 target genes. These studies will provide definitive in vivo evidence of the role of negative feedback of IGF-1 to the somatotroph and its relative importance in control of somatotroph function with respect to the neuroendocrine factors, GHRH and somatostatin. This design will also give insight into the contribution of IGF-1 in hypothalamic feedback in the control of somatotroph function. Relevance to public health: Despite medical advances in the treatment of growth disorders with GH and IGF-1, a clear understanding of their relative contributions to somatic growth and the mechanisms of action remain elusive. This proposal aims to perturb this system to study the associated changes in growth and hormone secretion; therefore providing better insight into the regulation of normal and abnormal growth. In the future, this may provide the basis for guidelines for the evaluation and treatment of children with growth disorders.

描述（由申请人提供）：生长激素-胰岛素样生长因子-1 （GH-IGF-1）轴在控制人类生长中起关键作用，该轴的改变通常导致生长迟缓。垂体前叶生长激素的合成和分泌受来自下丘脑的刺激性生长激素释放激素（GHRH）和抑制性生长抑素（SST）的控制。生长激素的许多作用是通过刺激IGF-1的产生介导的。虽然IGF-1已被证明对生长缺陷细胞有负反馈作用，但生长激素调节的确切生理机制尚不清楚。为了增加我们对IGF-1在生长激素调节中的中心反馈作用的理解，本提案的目标是创建缺乏生长激素上IGF-1受体（IGF-1 R）的敲除小鼠。具体目标#1将涉及使用cre/lox系统创建敲除动物；在igf - 1r位点含有loxP位点的动物将与携带rGHpCre重组酶转基因的小鼠交配。仔细记录基因型和确认有效的重组酶活性（生长激素和igf - 1r的免疫细胞化学），以及记录生长和发育的血液参数，以及激素水平的测量，将与生长激素特异性IGF-1受体敲除（SIRK）和对照小鼠一起进行。Specific Aim #2旨在通过刺激测试下丘脑因子、人类生长激素释放激素（GHRH）和生长抑素的释放，为IGF-1反馈的神经内分泌作用提供证据。此外，为了深入了解IGF-1负反馈的分子机制，我们将采用定量逆转录酶PCR来测定IGF-1靶基因的mRNA水平。这些研究将提供明确的体内证据，证明IGF-1负反馈对生长激素的作用，以及它在控制生长激素功能方面相对于神经内分泌因子、GHRH和生长抑素的重要性。该设计还将深入了解IGF-1在控制生长功能的下丘脑反馈中的作用。与公共卫生的相关性：尽管生长激素和IGF-1在治疗生长障碍方面取得了医学进展，但对它们对体细胞生长的相对贡献及其作用机制的清晰认识仍然难以捉摸。本研究旨在通过干扰该系统来研究生长和激素分泌的相关变化；因此，更好地了解正常和异常生长的调节。在未来，这可能为儿童生长障碍的评估和治疗提供指导依据。