REGULATION OF CBFA1 EXPRESSION

我们研究的长期目标是了解骨骼中控制细胞分化的分子基础，特别是成骨细胞谱系。Cbfa1是目前已知的唯一一种转录因子，它的存在是胚胎发生过程中成骨细胞分化所必需的。本申请中提出的实验旨在确定控制Cbfa1表达的顺式作用元件和反式作用因子。我们相信，这些知识将导致更好地理解诱导成骨细胞谱系中的细胞承诺和分化的分子机制，从而促进成骨。这反过来将有助于设计新的治疗方法，用于治疗由成骨细胞分化和功能受损引起的遗传性或退行性疾病。其具体目的是：-描述存在于近端2.2kb Cbfa1启动子片段中的成骨细胞特异性顺式作用元件(S)。-进行DNA结合分析，以确定与2.2.-kb Cbfa1启动子片段中存在的细胞特异性顺式作用元件结合的转录因子。-分析2.2kb Cbfa1近端启动子及其包含的顺式作用元件在转基因小鼠中的功能。-鉴定位于2.2.-kb近端Cbfa1启动子外的其他细胞特异性增强子元件。

The long term goal of our research is to understand the molecular basis controlling cell differentiation in the skeleton with a particular emphasis on the osteoblast lineage. Cbfa1 is the only known transcription factor whose presence is absolutely required for osteoblast differentiation during embryogenesis. The experiments proposed in this application aim at identifying the cis-acting elements and trans-acting factors controlling Cbfa1 expression. We believe that this knowledge will lead to a better understanding of the molecular mechanisms inducing cell commitment and differentiation along the osteoblast lineage and therefore of osteogenesis. This in turn will help to design new therapeutic approaches for treatment of genetic or degenerative diseases caused by impaired osteoblast differentiation and function. The specific aims are: - To delineate the osteoblast-specific cis-acting element(s) present in the proximal 2.2-kb Cbfa1 promoter fragment. - To perform DNA-binding assays to identify the transcription factors binding to the cell-specific cis-acting elements present in the 2.2.-kb Cbfa1 promoter fragment. - To analyze the function of the 2.2-kb Cbfa1 proximal promoter and of the cis-acting elements it contains in transgenic mice. - To identify other cell-specific enhancer elements located outside the 2.2.-kb proximal Cbfa1 promoter.