NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS
NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS
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
关键词:
DNA footprinting binding proteins cell growth regulation cell proliferation gel mobility shift assay gene expression genetic promoter element genetic regulatory element genetic transcription insulinlike growth factor molecular site mutant osteocytes protein structure function southern blotting tissue /cell culture transfection western blottings
中文摘要
描述(来自应用程序):
细胞更新对于骨重建和修复过程是必不可少的,
在一生中都会发生。细胞更新的损害被认为是一种
老年(II型)发病的分子机制
骨质疏松。胰岛素样生长因子(IGF)在糖尿病中的重要性
以下主要发现强调了骨骼细胞的更新:1)IGFS
是由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,以及3)IGFS
40%对体外培养的基底骨细胞增殖有抑制作用。尽管政府间金融服务机构的行动
在骨骼细胞更新中可以受到许多IGF系统的调节
组件,本提案侧重于一个IGF系统组件,即IGF
结合蛋白4(IGFBP-4)。我们最近的研究结果强调,
IGFBP-4的表达可能部分参与了受损的骨骼细胞
骨质疏松等疾病的更新:第一,IGFBP-4水平在
骨细胞条件培养液与骨细胞呈负相关
增殖率。第二,抑制内源性IGFBP-4的产生有
已被证明能刺激骨细胞的增殖。第三,血清IGFBP-4
在II型骨质疏松症合并髋关节的患者中,水平随着年龄的增长而升高
骨折。基于这样一个前提,即调控的分子机制
IGFBP-4的表达对我们理解IGFBP-4的作用至关重要
在骨骼细胞更新方面,我们提出了一项研究,以表征一种
一种涉及特定负面监管的负面监管机制
IGFBP-4基因第一外显子中存在NRE元件。在建议的
研究,IGFBP-4 NRE与之相互作用的精确序列(S)
蛋白质(S)以细胞特有的方式将由足迹决定
分析、凝胶迁移率漂移分析和西南分析。
随后,NRE中DNA-蛋白质相互作用的位置将是
系统突变并包含在IGFBP-4启动子-报告基因中
用于功能研究的结构。IGFBP-4启动子的差异
使用含有启动子的野生型和突变型NRE构建物的活性将
在瞬时转染骨细胞后进行评估
不同水平的IGFBP-4mRNA和蛋白的表达。预计
证实了NRE与特定基因之间相互作用的假设
结合蛋白参与负转录调控
IGFBP-4基因在不同细胞类型中的表达可以导致更好的
对老年性骨质疏松症发病机制的认识
通过抑制促进细胞更新的新疗法的开发
IGFBP-4在骨质疏松等疾病中的表达。
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)
专著(0)
科研奖励(0)
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:
IGFBP 4 PROTEASE AND HUMAN OSTEOBLASTS
-
批准号:6171427
-
项目类别:
-
资助金额:$15.44万
-
财政年份:1999
-
负责人:Xuezhong Qin
-
依托单位:
IGFBP 4 PROTEASE AND HUMAN OSTEOBLASTS
-
批准号:2904795
-
项目类别:
-
资助金额:$16.41万
-
财政年份:1999
-
负责人:Xuezhong Qin
-
依托单位:
IGFBP 4 PROTEASE AND HUMAN OSTEOBLASTS
-
批准号:6532973
-
项目类别:
-
资助金额:$16.38万
-
财政年份:1999
-
负责人:Xuezhong Qin
-
依托单位:
STRUCTURAL AND FUNCTIONAL ANALYSIS OF HUMAN IGFBP-4
-
批准号:2713292
-
项目类别:
-
资助金额:$3.09万
-
财政年份:1997
-
负责人:Xuezhong Qin
-
依托单位:
STRUCTURAL AND FUNCTIONAL ANALYSIS OF HUMAN IGFBP-4
-
批准号:2015424
-
项目类别:
-
资助金额:$3.04万
-
财政年份:1997
-
负责人:Xuezhong Qin
-
依托单位:
NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS
-
批准号:2769700
-
项目类别:
-
资助金额:$6.3万
-
财政年份:1997
-
负责人:Xuezhong Qin
-
依托单位:
NEGATIVE REGULATION OF IGFBP-4 EXPRESSION IN BONE CELLS
-
批准号:2470384
-
项目类别:
-
资助金额:$6.3万
-
财政年份:1997
-
负责人:Xuezhong Qin
-
依托单位:
海外基金