Physiologic Role of the Somatotroph IGF-1 Receptor

生长激素 IGF-1 受体的生理作用

基本信息

  • 批准号:
    7485305
  • 负责人:
  • 金额:
    $ 5.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)轴在控制人体生长方面起关键作用,该轴的改变通常导致生长迟缓。垂体前叶生长激素细胞合成和分泌生长激素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。GH的许多作用是通过刺激IGF-1的产生来介导的。虽然IGF-1已被证明对生长激素细胞具有负反馈作用,但GH调节的确切生理机制尚不清楚。为了增加我们对IGF-1对促生长素调节的中心反馈作用的理解,本提案的目标是创建缺乏促生长素上的IGF-1受体(IGF-1 R)的敲除小鼠。具体目标#1将涉及使用cre/lox系统产生敲除动物;在IGF-1 R基因座处含有loxP位点的动物将与携带rGHpCre重组酶转基因的小鼠交配。将使用生长激素特异性IGF-1受体敲除(SIRK)小鼠和对照小鼠仔细记录基因型并确认有效重组酶活性(GH和IGF-1 R的免疫细胞化学),沿着记录生长和发育的辅助学参数以及激素水平的测量。具体目标#2旨在通过激发性测试下丘脑因子、人生长激素释放激素(GHRH)和生长抑素的释放,提供IGF-1反馈的神经内分泌作用的证据。此外,为了深入了解IGF-1负反馈的分子机制,将进行定量逆转录酶PCR以确定IGF-1靶基因的mRNA水平。这些研究将提供明确的体内证据的负反馈的IGF-1的促生长素的作用和它的相对重要性,在控制促生长素功能的神经内分泌因子,GHRH和生长抑素。该设计还将深入了解IGF-1在下丘脑反馈中控制生长激素功能的贡献。与公共卫生的相关性:尽管在生长激素和IGF-1治疗生长障碍方面取得了医学进展,但对它们对躯体生长的相对贡献和作用机制的清晰理解仍然难以捉摸。该提案旨在扰乱这一系统,以研究生长和激素分泌的相关变化,从而更好地了解正常和异常生长的调节。在未来,这可能为评估和治疗生长障碍儿童的指南提供基础。

项目成果

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Christopher Joseph Romero其他文献

Christopher Joseph Romero的其他文献

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{{ truncateString('Christopher Joseph Romero', 18)}}的其他基金

The role of central IGF- 1 feedback in the regulation of growth and metabolism
中枢IGF-1反馈在生长和代谢调节中的作用
  • 批准号:
    8110929
  • 财政年份:
    2011
  • 资助金额:
    $ 5.89万
  • 项目类别:
The role of central IGF- 1 feedback in the regulation of growth and metabolism
中枢IGF-1反馈在生长和代谢调节中的作用
  • 批准号:
    8461939
  • 财政年份:
    2011
  • 资助金额:
    $ 5.89万
  • 项目类别:
The role of central IGF- 1 feedback in the regulation of growth and metabolism
中枢IGF-1反馈在生长和代谢调节中的作用
  • 批准号:
    8254455
  • 财政年份:
    2011
  • 资助金额:
    $ 5.89万
  • 项目类别:
The role of central IGF- 1 feedback in the regulation of growth and metabolism
中枢IGF-1反馈在生长和代谢调节中的作用
  • 批准号:
    8662757
  • 财政年份:
    2011
  • 资助金额:
    $ 5.89万
  • 项目类别:
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
  • 财政年份:
    2008
  • 资助金额:
    $ 5.89万
  • 项目类别:

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