Mineralization: Integrins and Focal Adhesion Kinase

矿化：整合素和粘着斑激酶

基本信息

批准号：
6625686
负责人：
GALEN B SCHNEIDER
金额：
$ 7.37万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-03-01 至 2005-02-28
项目状态：
已结题

项目摘要

Osteogenesis involves the recruitment of multi-potential mesenchymal stem cells and the progressive differentiation of these cells into osteoblasts. Osteoblast differentiation and skeletal formation during embryonic development is mediated by an essential transcription factor protein core binding core binding factor-alpha1 (cbfa1). Integrin receptors are widely expressed and bind extracellular matrix proteins. They also regulate intracellular signaling pathways that contribute to the development of cranial-facial structures, wound healing, cell motility, cell growth and differentiation, and apoptosis. Signaling pathways and proteins mediated by integrins, such as the focal adhesion tyrosine kinase FAK, can regulate cell growth and differentiation, as well as cell fate. Yet the role of integrin receptor mediation of osteoblast differentiation and subsequent mineralization is not fully understood. Adhesion- mediated signaling transduced through osteoblast-extracellular matrix interactions during osteogenesis may represent essential pathways for processing environmental cues necessary for gene expression, as well as bone formation and remodeling during osteoblast differentiation. The goal of this proposal is to determine if the integrin associated protein tyrosine kinase FAK mediates osteogenic gene expression (Cbfa1, BSP, Collagen type I), and subsequent mineralization. We hypothesize that blocking the interaction of various osteoblast integrin receptors with their underlying extracellular matrix with specific antibodies will affect gene expression and minerization. We also predict that over-expressing the integrin associated protein tyrosine kinase FAK in a non- mineralizing. We also predict that over-expressing the integrin associated protein tyrosine kinase FAK in a non-mineralizing OB clones will lead to mineralization. We will use histological, biochemical, and molecular approaches to perform these studies. Data acquired from these studies will allow us to better understand how osteoblast differentiation and osteogenesis are mediated through integrin receptors and associated signaling proteins such as FAK. This will allow for development of new therapeutic approaches that in turn could lead to novel treatments and tissue-engineered biological applications to increase the quality of life for many patients.

成骨涉及多潜能间充质干细胞的募集以及这些细胞逐渐分化为成骨细胞。胚胎发育过程中的成骨细胞分化和骨骼形成是由必需的转录因子蛋白核心结合因子-α1 (cbfa1) 介导的。整合素受体广泛表达并结合细胞外基质蛋白。它们还调节细胞内信号传导途径，有助于颅面结构的发育、伤口愈合、细胞运动、细胞生长和分化以及细胞凋亡。由整合素介导的信号通路和蛋白质（例如粘着斑酪氨酸激酶 FAK）可以调节细胞生长和分化以及细胞命运。然而，整合素受体介导成骨细胞分化和随后矿化的作用尚不完全清楚。成骨过程中通过成骨细胞-细胞外基质相互作用转导的粘附介导的信号可能代表处理基因表达以及成骨细胞分化过程中骨形成和重塑所需的环境线索的重要途径。该提案的目标是确定整合素相关蛋白酪氨酸激酶 FAK 是否介导成骨基因表达（Cbfa1、BSP、I 型胶原）以及随后的矿化。我们假设用特异性抗体阻断各种成骨细胞整合素受体与其潜在细胞外基质的相互作用将影响基因表达和矿化。我们还预测，在非矿化过程中，整合素相关蛋白酪氨酸激酶 FAK 会过度表达。我们还预测，在非矿化 OB 克隆中过度表达整合素相关蛋白酪氨酸激酶 FAK 将导致矿化。我们将使用组织学、生化和分子方法来进行这些研究。从这些研究中获得的数据将使我们能够更好地了解成骨细胞分化和成骨是如何通过整联蛋白受体和相关信号蛋白（如 FAK）介导的。这将有助于开发新的治疗方法，进而带来新的治疗方法和组织工程生物应用，以提高许多患者的生活质量。