Control of IGF-1 Gene Transcription by Growth Hormone

描述(申请人提供)：胰岛素样生长因子-1(IGF-1)是一种保守的70个残基的分泌性蛋白质，在哺乳动物和其他脊椎动物的躯体生长中起着重要的作用。虽然已有大量证据支持IGF-1是一种主要的出生后生长因子，受生长激素(GH)调节，但许多研究表明，这种多肽具有更广泛的功能，包括在整个生命周期中对局部组织的生长、维持和修复的作用，以及对癌症和衰老的有害影响。这些观察结果反过来暗示，不仅对IGF-1合成的控制可能是多因素的，而且每个调控途径可能在生长、发育和疾病的不同方面发挥关键作用。作为了解IGF-1在不同生理条件下的合成和作用机制的长期努力的一部分，应用的重点将是GH对IGF-1基因转录的调控。主要目标将是确定生长激素通过转录因子StatSb控制IGF-1表达的分子机制。为此，我们提出了以下4个具体目标：1.明确GH通过StatSb激活IGF-1基因转录的起始步骤。2.研究生长激素抑制胰岛素样生长因子-1转录的机制。3.确定胰岛素样生长因子-1基因的HS7区域是否是调节生长激素调节的胰岛素样生长因子-1基因激活的充分必要条件。4.研究人类StatSb中一种天然氨基酸替代功能障碍的机制，该功能障碍与严重的生长障碍有关。

DESCRIPTION (provided by applicant): Insulin-like growth factor-1 (IGF-1), a conserved 70-residue secreted protein, plays a fundamental role in somatic growth in mammals and other vertebrate species. Although much evidence has accumulated supporting IGF-1 as a major postnatal growth factor, regulated by growth hormone (GH), many studies have suggested a broader range of functions for this peptide, including actions on local tissue growth, maintenance, and repair throughout the life span, as well as deleterious effects in cancer and aging. These observations in turn imply not only that control of IGF-1 synthesis may be multi-factorial, but also that each regulatory pathway may exert key critical actions on different aspects of growth, development, and disease. As part of a long-term effort to understand the mechanisms by which IGF-1 synthesis and action are controlled under different physiological conditions, the focus of the application will be on regulation of IGF-1 gene transcription by GH. Key goals will be to define the molecular mechanisms by which GH controls IGF-1 expression via the transcription factor, StatSb. Toward this end the following 4 Specific Aims are proposed: 1. To define the initial steps in activation of IGF-1 gene transcription by GH through StatSb. 2. To characterize mechanisms of termination of GH-stimulated IGF-1 transcription. 3. To determine if the HS7 region of the IGF-1 locus is both necessary and sufficient to mediate GH- regulated IGF-1 gene activation. 4. To characterize mechanisms of dysfunction of a natural amino acid substitution in human StatSb that is associated with profound growth failure.