Control of IGF-I Gene Transcription in Osteoblasts

描述（由申请人提供）：胰岛素样生长因子-I（IGF-I）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物种的体细胞生长中发挥重要作用。虽然已经积累了大量证据支持IGF-I作为主要的出生后生长因子，至少部分受生长激素调节，但许多研究表明这种肽具有更广泛的功能，包括在整个生命周期中对局部组织生长，维护和修复的作用。这些观察结果反过来又意味着IGF-I合成的控制可能是多因素的，不仅响应于全身激素信号，而且响应于组织特异性因素。IGF-I由包括成骨细胞在内的许多细胞产生，并且可以在骨骼以及其他组织中充当生长和分化因子。最近的研究表明IGF-I是甲状旁腺激素（PTH）对骨骼合成代谢作用的关键成分，并确定了PTH在增加骨量和预防骨质疏松症中的作用，这只强调了IGF-I在维持骨骼完整性方面的重要性。由于骨质疏松症是一种骨吸收超过骨形成的重塑疾病，因此任何对增强骨量的途径的见解都具有潜在的治疗意义。作为长期研究IGF-I合成在不同生理条件下的调控机制的一部分，本申请的重点将是骨细胞中IGF-I基因转录的调控。关键目标将是确定PTH通过环AMP和蛋白激酶A通过转录因子C/EBP δ控制IGF-I表达的信号转导途径和分子机制。为此，提出了以下四个具体目标：1。研究PKA如何激活C/EBP δ并刺激其在成骨细胞核内的表达.确定PKA如何促进骨细胞中C/EBP δ的转录活性.目的：探讨成骨细胞中IGF-1转录终止和C/EBP δ活性下调的机制.目的通过基因表达谱分析，探讨C/EBP δ在成骨细胞生物学中的作用。

DESCRIPTION (provided by applicant): Insulin-like growth factor-I (IGF-I), 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-I as a major postnatal growth factor, regulated at least in part by growth hormone, 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. These observations in turn imply that control of IGF-I synthesis may be multi-factorial, responding not only to systemic hormonal signals but also to tissue-specific factors. IGF-I is produced by many cells including osteoblasts, and can act as a growth and differentiation factor within the skeleton as well as in other tissues. Recent studies implicating IGF-I as a key component of the anabolic effects of parathyroid hormone (PTH) on bone and establishing a role for PTH in increasing bone mass and preventing osteoporosis only underscore the importance of IGF-I in maintaining skeletal integrity. Since osteoporosis is a disorder of remodeling in which bone resorption outstrips formation, any insights into pathways that enhance bone mass have potential therapeutic implications. As part of a long-term effort to understand the mechanisms by which IGF-I synthesis is controUed under different physiological conditions, the focus of this application will be on regulation of IGF-I gene transcription in bone cells. Key goals will be to define the signal transduction pathways and molecular mechanisms by which PTH through cyclic AMP and protein kinase A controls IGF-I expression via the transcription factor, C/EBPdelta. Toward this end the following four Specific Aims are proposed:1. To determine how PKA activates C/EBPdelta and stimulates its nuclear expression in osteoblasts.2. To establish how PKA promotes the transcriptional activity of C/EBPdelta in bone cells.3. To define mechanisms of termination of hormone-activated IGF-I transcription and down regulation of C/EBPdelta activity in osteoblasts.4. To evaluate by gene profiling the role of C/EBPdelta in osteoblast biology.