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NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS

NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS
骨细胞中 IGFBP-4 表达的负调控
批准号:
6055679
负责人:
Xuezhong Qin
金额:
$6.3万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1997
资助国家:
美国
项目状态:
已结题
起止时间:
1997-09-25 至 2000-08-31

项目摘要

项目成果

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中文摘要
翻译
描述(来自应用程序): 细胞更新对于骨重建和修复过程至关重要, 发生在一生中。 细胞更新的损害已被确定为 老年性(II型)糖尿病发病的分子机制 骨质疏松 胰岛素样生长因子(IGFs)在 以下关键发现强调了骨骼细胞的更新:1)IGFs 是骨细胞产生的最丰富的有丝分裂原,2)IGF是重要的 骨细胞增殖的刺激物,和3)IGFs贡献约 40%对体外培养的基底骨细胞增殖有抑制作用。 虽然政府间论坛的行动 在骨骼细胞更新中,可以通过许多IGF系统来调节 本提案侧重于互联网治理论坛系统的一个组成部分,即互联网治理论坛 结合蛋白4(IGFBP-4)。 我们最近的研究结果强调, IGFBP-4的表达可能在一定程度上导致骨骼细胞受损, 骨质疏松症等疾病中的IGFBP-4水平:首先, 骨细胞条件培养液与骨细胞 增殖率 第二,内源性IGFBP-4产生的抑制具有 能刺激骨细胞增殖 三、血清IGFBP-4 水平随着年龄的增长而升高,在II型骨质疏松症患者中, 骨折 基于这样的前提, IGFBP-4的表达对于我们理解IGFBP-4的作用至关重要 在骨骼细胞更新中,我们已经提出了研究来表征 负调节机制,涉及特定的负调节 IGFBP-4基因第一外显子存在一个NRE元件。 拟议 研究中,IGFBP-4 NRE中与IGFBP-4相互作用的精确序列 以细胞特异性方式的蛋白质将通过足迹来确定 分析、电泳迁移率变动分析和西南分析。 随后,NRE中DNA-蛋白质相互作用的位点将被 系统突变并包含在IGFBP-4启动子报告基因中 用于功能研究的构建体。 IGFBP-4启动子的差异 使用含有启动子构建体的野生型和突变型NRE的活性将 在瞬时转染表达 不同水平的IGFBP-4 mRNA和蛋白。 预计各国 证实了NRE和特定的 结合蛋白有助于负转录调控 IGFBP-4基因在各种细胞类型中的表达可能导致更好的 对老年性骨质疏松症发病机制的认识, 开发新的治疗方法,通过抑制 IGFBP-4在骨质疏松症等疾病中的表达。
英文摘要
DESCRIPTION (from the application): Cell renewal is essential for bone remodeling and repair processes which occur throughout life. Impairment in cell renewal has been identified as a molecular mechanism responsible for the pathogenesis of senile (type II) osteoporosis. The importance of insulin-like growth factors (IGFs) in skeletal cell renewal is emphasized by the following key findings: 1) IGFs are the most abundant mitogens produced by bone cells, 2) IGFs are important stimulaters of bone cell proliferation, and 3) IGFs contribute approximately 40% to basal bone cell proliferation in vitro. Although the actions of IGFs in skeletal cell renewal can be modulated by a number of IGF system components, this proposal is focused on one IGF system component, namely IGF binding protein-4 (IGFBP-4). Our recent findings emphasize that changes in IGFBP-4 expression may in part contribute to the impaired skeletal cell renewal in diseases such as osteoporosis: First, IGFBP-4 levels in the conditioned medium of bone cells correlate negatively with the bone cell proliferation rate. Second, inhibition of endogenous IGFBP-4 production has been shown to stimulate bone cell proliferation. Third, serum IGFBP-4 levels are elevated with age and in type II osteoporosis patients with hip fracture. Based on the premise that molecular mechanisms which regulate IGFBP-4 expression are crucial to our understanding of the role of IGFBP-4 in skeletal cell renewal, we have proposed studies to characterize a negative regulatory mechanism which involves a specific negative regulatory element (NRE) present in the first exon of IGFBP-4 gene. In the proposed studies, the precise sequence(s) in the IGFBP-4 NRE which interact with protein(s) in a cell specific manner will be determined by footprint analysis, electrophoretic mobility shift analysis and Southwestern analysis. Subsequently, the sites of DNA-protein interaction in the NRE will be systematically mutated and included in the IGFBP-4- promoter-reporter constructs used for functional studies. The differences in IGFBP-4 promoter activity using wild type and mutant NRE containing promoter constructs will be evaluated after transient transfection of bone cells which express varying levels of IGFBP-4 mRNA and protein. It is anticipated that confirmation of the hypothesis that interaction between the NRE and specific binding proteins contribute to negative transcriptional regulation of IGFBP-4 gene expression in various cell types could lead to a better understanding of the pathogenesis of senile osteoporosis and to the development of novel therapies to increase cell renewal by suppressing IGFBP-4 expression in diseases such as osteoporosis.
期刊论文(1)
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会议论文
DOI: 10.1210/jcem.86.2.7223
发表时间: 2001-02
期刊: The Journal of clinical endocrinology and metabolism
影响因子: --
作者: [D. Byun;S. Mohan;M. Yoo;C. Sexton;D. Baylink;X. Qin]
通讯作者: D. Byun;S. Mohan;M. Yoo;C. Sexton;D. Baylink;X. Qin
Role and Regualtion of miRNA223 in EAE
  • 批准号:
    8812720
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2014
  • 负责人:
    Xuezhong Qin
  • 依托单位:
Role and Regualtion of miRNA223 in EAE
  • 批准号:
    8635212
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2014
  • 负责人:
    Xuezhong Qin
  • 依托单位:
Role and Regualtion of miRNA223 in EAE
  • 批准号:
    8974335
  • 项目类别:
  • 资助金额:
    $0.0万
  • 财政年份:
    2014
  • 负责人:
    Xuezhong Qin
  • 依托单位:
IGFBP 4 PROTEASE AND HUMAN OSTEOBLASTS
  • 批准号:
    6375098
  • 项目类别:
  • 资助金额:
    $15.9万
  • 财政年份:
    1999
  • 负责人:
    Xuezhong Qin
  • 依托单位:
海外基金