DLX GENE REGULATION OF OSTEOBLAST DIFFERENTIATION

成骨细胞分化的 DLX 基因调控

• 批准号: 6778677
• 负责人: Alexander C Lichtler
• 金额: $ 30.87万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778677
• 关键词: DNA binding protein; RNA interference; biological signal transduction; bone development; cell differentiation; craniofacial; gene induction /repression; gene targeting; genetic promoter element; genetic regulation; genetically modified animals; in situ hybridization; laboratory mouse; microarray technology; northern blottings; osteoblasts; skeletal system

DESCRIPTION (provided by applicant): The goal of our studies is to contribute to the understanding of the transcriptional regulation of osteoblastic differentiation. This is crucial to our understanding of the mechanisms controlling bone formation. Greater understanding of this process may lead to more rational design of therapies for osteoporosis and other bone diseases. Our studies and those of others have suggested that Dlx5, a homeodomain-containing transcription factor, plays an important role in the induction of osteoblastic differentiation. The Specific Aims of this grant application are: 1. To assess the role of Dlx5 in osteoblast differentiation in vivo by studying the effect of over expression of Dlx5 in osteoblasts off transgenic mice at different stages of osteoblast lineage progression. 2. To study the effect of inactivation of Dlx5 in cultured osteoblasts, and to assess the effect of Dlx5 on osteoblastic gene expression. We will study in vitro differentiation of osteoblasts derived from Dlx5 knockout mice. We will also carry out focused microarray analysis of cells plus and minus Dlx5 to identify genes that are induced or inhibited by Dlx5, and analyze bone development in an osteoblast directed knockout of the Dlx5 gene. This will allow us to separate the effects of Dlx5 expression in osteoblasts from the effect of this gene in other cell types. 3. To assess the potential for other members of the Dlx gene family to contribute to induction of osteoblast differentiation in vivo. We will continue to examine the expression of Dlx1, 2,3, 6 and 7 in osteoblasts. We will continue studies on Dlx3, which we already have detected in differentiating osteoblasts. We will continue studies on the ability of other Dlx genes to induce osteoblastic differentiation in the same in vitro system that we have used to study Dlx5. We will also study an osteoblast-directed knockout of the Dlx3 gene, to evaluate the role of Dlx3 in bone development in vivo. Our proposed studies will contribute to a more complete understand of the role of the Dlx protein family in osteoblast differentiation.

描述(由申请人提供)： 我们的研究目的是帮助理解成骨细胞分化的转录调控。这对于我们理解骨形成的控制机制是至关重要的。对这一过程的更多了解可能会导致更合理地设计治疗骨质疏松症和其他骨骼疾病的方法。我们和其他人的研究表明，Dlx5是一种含有同源结构域的转录因子，在诱导成骨细胞分化中发挥着重要作用。本资助申请的具体目的是：1.通过研究Dlx5在转基因小鼠成骨细胞中过表达对成骨细胞谱系发育不同阶段的影响，评价Dlx5在体内成骨细胞分化中的作用。2.研究Dlx5失活对成骨细胞的影响，探讨Dlx5对成骨细胞基因表达的影响。我们将研究Dlx5基因敲除小鼠来源的成骨细胞的体外分化。我们还将对细胞正负Dlx5进行聚焦微阵列分析，以确定Dlx5诱导或抑制的基因，并分析成骨细胞定向敲除Dlx5基因的骨发育。这将使我们能够将Dlx5基因在成骨细胞中表达的影响与该基因在其他类型细胞中的影响分开。3.评估DLX基因家族其他成员在体内诱导成骨细胞分化的可能性。我们将继续检测Dlx1、2、3、6和7在成骨细胞中的表达。我们将继续研究DLX3，我们已经检测到DLX3在成骨细胞分化中的作用。我们将在研究Dlx5的同一体外系统中继续研究其他DLX基因诱导成骨细胞分化的能力。我们还将研究成骨细胞定向的DLX3基因敲除，以评估DLX3在体内骨发育中的作用。我们提出的研究将有助于更全面地了解DLX蛋白家族在成骨细胞分化中的作用。