Control of IGF-1 Gene Transcription by Growth Hormone

生长激素对 IGF-1 基因转录的控制

• 批准号: 7230524
• 负责人: Peter S Rotwein
• 金额: $ 29.87万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230524
• 关键词: Age; Aging; Amino Acid Substitution; Condition; Disease; Failure; Functional disorder; Gene Activation; Genetic Transcription; Goals; Growth; Growth Factor; Growth and Development function; Human; Insulin-Like Growth Factor I; Longevity; Maintenance; Malignant Neoplasms; Mammals; Mediating; Molecular; Peptides; Physiological; Play; Proteins; Range; Regulation; Regulatory Pathway; Research Personnel; Role; Somatomedins; Somatotropin; postnatal; programs; repaired; transcription factor

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.

描述（由申请人提供）：一种保守的70个残基分泌蛋白质胰岛素样生长因子1（IGF-1），在哺乳动物和其他脊椎动物物种的体细胞生长中起着基本作用。尽管许多证据积累了支持IGF-1作为受生长激素（GH）调节的主要产后生长因子，但许多研究表明，该肽的功能范围更广泛，包括对局部组织生长，维持整个生命周期的行动，以及在整个生命周期中的维护，以及在癌症和衰老中的有害作用。这些观察结果反过来不仅意味着对IGF-1合成的控制可能是多因素的，而且每个监管途径也可能对生长，发育和疾病的不同方面作出关键的关键作用。作为理解IGF-1合成和作用在不同生理条件下控制的机制的长期努力的一部分，应用的重点将放在GH对IGF-1基因转录的调节上。关键目标将是定义GH通过转录因子STATSB控制IGF-1表达的分子机制。为此，提出了以下4个特定目标：1。定义GH通过STATSB激活IGF-1基因转录的初始步骤。 2。表征GH刺激的IGF-1转录的终止机制。 3。确定IGF-1基因座的HS7区域是否既需要又足以介导GH-调节的IGF-1基因激活。 4。表征人类Statsb中天然氨基酸替代功能障碍的机制，与深远的生长失败有关。