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: 7364414
• 负责人: Peter S Rotwein
• 金额: $ 13.85万
• 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/7364414
• 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

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 four 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.

胰岛素样生长因子1（IGF-1）是一种保守的70个残基分泌蛋白，在 哺乳动物和其他脊椎动物的体细胞生长。尽管有很多证据积累 支持IGF-1是由生长激素（GH）调节的主要产后生长因子，许多研究具有 该肽提出了更广泛的功能，包括对局部组织生长的作用， 在整个生命周期内进行维护和修复，以及在癌症和衰老中的有害影响。这些 反过来，观察不仅暗示了对IGF-1合成的控制可能是多因素的，而且也可能是 监管途径可能会对生长，发育和疾病的不同方面作出关键的关键行动。 作为理解IGF-1合成和作用的机制的长期努力的一部分 在不同的生理条件下控制，应用的重点将放在IGF-1的调节上 GH的基因转录。关键目标是定义GH控制IGF-1的分子机制 通过转录因子STATSB的表达。为此，以下四个具体目标是 建议的： 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。表征人类属性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。