Bone Cell Growth Regulation by Runx2/Cbfa1

描述（由申请方提供）：间充质细胞、骨祖细胞和未成熟成骨细胞增殖性扩增的严格阳性和阴性对照对于正常骨骼发育和骨形成至关重要。矿化骨骼的形成需要runt相关的转录因子RUNX 2/CBFA 1，但新的证据表明，其生物学功能超出了成骨细胞成熟。我们的中心假设是RUNX 2/CBFA 1是成骨细胞增殖的主要调节因子。这个假设将通过调查三个相关的问题来解决。首先，RUNX 2蛋白的失活是否会遗传性地影响骨祖细胞的细胞生长参数（目的1）？拟议的研究将检查RUNX 2的失活是否改变RUNX 2缺陷的颅骨细胞的细胞生长特性，以及重新引入RUNX 2是否恢复正常的细胞生长控制。第二，RUNX 2的哪种转录辅助调节因子介导其成骨细胞增殖相关的生物学功能（目的2）？RUNX 2与几种不同的辅因子相互作用，调节其基因调控活性。为了解决这个问题，关键的共调节因子，连同RUNX 2介导的骨细胞生长调节的特点。第三，哪些RUNX 2调节基因有助于成骨细胞的生长控制（目的3）？这个问题将通过鉴定与RUNX 2一起介导RUNX 2的增殖相关调控特性的RUNX 2下游靶基因来解决。这些研究的结果将为RUNX 2依赖的分子机制和控制成骨细胞增殖的基因调控程序提供关键见解。了解控制骨细胞生长的机制可能允许操纵其细胞生长潜力，用于骨骼疾病、骨折和/或骨定向基因治疗的临床应用。

DESCRIPTION (provided by applicant): Stringent positive and negative control of the proliferative expansion of mesenchymal cells, osteoprogenitor cells and immature osteoblasts is critical for normal skeletal development and bone formation. Formation of a mineralized skeleton requires the runt-related transcription factor RUNX2/CBFA1, but new evidence indicates that its biological function extends beyond that in osteoblast maturation. Our central hypothesis is that RUNX2/CBFA1 is a principal regulator of osteoblast proliferation. This hypothesis will be addressed by investigating three related questions. First, does inactivation of the RUNX2 protein genetically influence cell growth parameters in osteoprogenitors (Aim 1)? The proposed studies will examine whether inactivation of RUNX2 alters cell growth characteristics of RUNX2 deficient calvarial cells, and whether re-introduction of RUNX2 restores normal cell growth control. Second, which transcriptional co-regulator of RUNX2 mediates its osteoblast proliferation-related biological functions (Aim 2)? RUNX2 interacts with several distinct co-factors that modulate its gene regulatory activity. To address this question, the critical co-regulatory factor that together with RUNX2 mediates bone cell growth regulation will be characterized. Third, which RUNX2 regulated genes contribute to growth control of osteogenic cells (Aim 3)? This question will be addressed by identifying downstream target genes of RUNX2 that together with RUNX2 mediate the proliferation-related regulatory properties of RUNX2. The results of these studies will provide key insights into the RUNX2 dependent molecular mechanisms and gene regulatory programs that control osteoblast proliferation. Understanding the mechanisms by which growth of osseous cells is controlled may permit manipulation of their cell growth potential for clinical applications in the treatment of skeletal diseases, bone fractures and/or bone-directed gene therapy.