BIOLOGY OF CELL/CELL COMMUNICATION IN BONE

骨骼重塑的特征是细胞间的沟通， 成骨细胞和成骨细胞前体之间的网络， 分化的骨形成成骨细胞和骨吸收破骨细胞， 所有这些都是由与骨基质的复杂相互作用控制的 蛋白质和局部和局部之间的旁分泌-内分泌-自分泌相互作用， 全身性骨营养因子。这个多学科研究计划 将应用细胞和分子生物学的技术和概念， 分析对骨营养因子的生物反应的细胞模型， 并探讨细胞-细胞和细胞-基质相互作用在细胞凋亡中的作用。 这些反应的传导。为了实现这些目标，我们 本文拟：（1）分析整合素与基质蛋白的关系 成骨细胞的生长和分化， 细胞因子和生长因子对其的影响;并确定关键的 信号转导途径介导的相互作用， 整合素、基质蛋白和成骨细胞功能;（ii）分析整合素、基质蛋白和成骨细胞功能的作用。 破骨细胞活化中金属蛋白酶和基质裂解的作用 确定激活的结构要求的目标， 表征活化所必需的破骨细胞受体，和 确定空泡H+ ATP酶极化在骨坏死中的作用 和成骨细胞活性反应;（iii）分析整合素在 对机械应变的反应，因为它们参与了 人成骨细胞中的合成代谢信号和细胞骨架变化;（iv） 确定破骨细胞衍生的趋化因子谱，并分析激素， 成骨细胞发育的细胞因子和基质依赖性调节， 迁移和功能;和（v）鉴定和表征趋化因子 受体作为成骨细胞分化的函数， 活动一个专门的资源中心指定为“细胞生物学 核心实验室”将提供实验性的协助和咨询， 设计，制备适当的细胞培养物，免疫化学， 细胞因子ELISA，原位杂交技术支持 分析和cDNA探针的集中储存库。

Skeletal remodeling is characterized by an intercellular communicating network between osteoclastic and osteoblastic precursors and more differentiated bone forming osteoblast and the bone resorbing osteoclast, all of which is controlled by a complex interaction with bone matrix proteins and a paracrine-endocrine-autocrine interplay between local and systemic osteotrophic factors. This multidisciplinary research program will apply the techniques and concepts of cell and molecular biology to analyze cellular models of biological responses to osteotrophic factors, and to pursue the role of cell-cell and cell-matrix interactions in the transduction of these responses. In order to achieve these goals we propose to: (i) analyze the relationships between integrins-matrix protein interactions to the growth and differentiation of osteoblasts and the effects of cytokines and growth factors thereon; and to identify pivotal signal transduction pathways which mediate the interactions between integrins, matrix proteins and osteoblast function; (ii) analyze the role of metalloproteinases and matrix cleavage in osteoclast activation with the goals of identifying the structural requirements for activation, characterizing the osteoclast receptors necessary for activation, and determining the role of vacuolar H+ATPase polarization in the osteoclastic and osteoblastic activity response; (iii) analyze the role of integrins in response to mechanical strain as they participate in the generation of anabolic signals and cytoskeletal changes in the human osteoblast; (iv) to define a profile of osteoclast-derived chemokines and to analyze hormonal, cytokine and matrix-dependent modulation of osteoblast development, migration and function; and (v) to identify and characterize the chemokine receptors on osteoblasts as a function of osteoblast differentiation and activity. A specialized resource center designated as the "Cell Biology Core Laboratory" will provide assistance and consultation in experimental designs, preparation of appropriate cell cultures, immunochemistry,, ELISAs for cytokines, technical support for in situ hybridization analyses, and a centralized repository for cDNA probes.