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IDENTIFICATION OF A BONE SPECIFIC FUNCTION FOR P53

P53 骨骼特异性功能的鉴定

基本信息

批准号：
6406076
负责人：
NALINI CHANDAR
金额：
$ 1.6万
依托单位：
MIDWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2001-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6406076
关键词：
bone metabolism cell differentiation gene expression gene induction /repression genetic regulation genetically modified animals insulinlike growth factor laboratory mouse osteoblasts osteocalcin tumor suppressor proteins

项目摘要

DESCRIPTION: The long-term goal of this application is to investigate the role of p53 in osteoblast differentiation, a process central to bone formation. Toward this goal, studies are proposed aimed at clarifying when and how p53 might function in this pathway. The role of p53 in the regulation of osteocalcin gene expression and other genes involved in bone differentiation will be investigated. The role of mdm-2, a downstream effector of p53, in osteocalcin gene regulation will be studied. Alterations in p53 expression and transactivation activity will be followed during in vitro bone differentiation to determine the stage and time at which induction of mdm-2 may result in osteocalcin expression. Other studies will address the question of whether p53-independent mdm-2 forms can function in this regulation, in the absence of p53. The applicant will also determine if p53 modulates the activity of the Insulin Like Growth Factor Binding Protein-3 and Bone Morphogenetic Protein-2 expression, during bone differentiation. Wherever possible the studies will be substantiated using osteoblasts from p53 heterozygous transgenic mice. The proposed studies are aimed at increasing our understanding of: 1) the exact mechanism of action of p53 in bone differentiation and osteocalcin gene regulation: 2) the role of mdm-2 as a transcriptional activator; 3) and the mechanisms by which p53 and mdm-2 genes may mediate bone maturation.

描述：该应用程序的长期目标是调查 p53 在成骨细胞分化（骨的核心过程）中的作用形成。为了实现这一目标，提出了一些研究，旨在澄清何时以及 p53 如何在该途径中发挥作用。 p53的作用骨钙素基因表达和其他骨相关基因的调节将进行差异化研究。下游 mdm-2 的作用将研究p53在骨钙素基因调控中的效应子。 p53 表达和反式激活活性的改变将被跟踪在体外骨分化期间确定阶段和时间 mdm-2 的诱导可能导致骨钙素表达。其他研究将解决独立于 p53 的 mdm-2 形式是否可以在缺乏 p53 的情况下，该调节发挥作用。申请人还将确定 p53 是否调节胰岛素样生长因子的活性骨形成过程中结合蛋白 3 和骨形态发生蛋白 2 的表达差异化。只要有可能，研究将通过以下方式得到证实：来自 p53 杂合转基因小鼠的成骨细胞。拟议的研究是旨在增加我们对以下方面的理解：1）确切的作用机制 p53在骨分化和骨钙素基因调控中的作用：2） mdm-2 作为转录激活剂； 3）以及p53的机制 mdm-2 基因可能介导骨成熟。