CONSTITUTIVELY ACTIVE PTH/PTHRP RECEPTORS IN OSTEOBLAST

说明：(摘自应用)：甲状旁腺激素是一种重要的生理 骨周转和钙稳态的调节剂。尽管有相当大的 尽管已有多项研究，但仍有许多关于 甲状旁腺激素在骨中的作用机制。体外和体内研究表明 甲状旁腺激素/甲状旁腺素受体在介导甲状旁腺激素中的重要作用 骨子里的动作。最近，我们建立了转基因小鼠模型(CL)，在 人甲状旁腺激素/甲状旁腺素rP受体在 小鼠α1(I)胶原基因启动子的调控。我们会利用这个优势 这一独特的模型来剖析一些潜在的 甲状旁腺素在骨中的合成代谢和分解代谢作用。通过将CL小鼠与 全身过度表达导致骨吸收受损的转基因小鼠 对于骨保护素(OPG)，我们将研究骨吸收是否是一种 甲状旁腺激素/甲状旁腺素受体诱导骨形成的先决条件(特定目的I)。通过 比较结构性表达A基因的转基因小鼠(OS)的表型 小鼠骨钙素基因调控的人甲状旁腺激素/甲状旁腺素受体活性 对于CL动物的表型启动子，我们将确定其作用 不同程度的成骨细胞/基质细胞上的PTH/PTHrP受体 差异化(特指II)。通过研究细胞的分化和活性 从CL的骨髓和骨膜分离出骨祖细胞 突变小鼠，然后移植到免疫缺陷小鼠，我们将评估 微环境在产生不同的反应性中的作用 这些细胞激活甲状旁腺素/甲状旁腺素受体(特异性目标III)。通过 用微阵列技术分析从成骨细胞和成骨细胞中提取的RNA 从CL突变小鼠和野生型小鼠中分离出更成熟的成骨细胞 ，我们将系统地研究已知和未知的基因 成骨细胞中甲状旁腺素/甲状旁腺素受体活化的调节 世系(特定目标四)。

DESCRIPTION: (Taken from the application): PTH is an important physiological regulator of bone turnover and calcium homeostasis. Despite the considerable number of studies, there are still many unanswered questions about the mechanism of action of PTH in bone. In vitro and in vivo studies have demonstrated the crucial role of the PTH/PTHrP receptor in mediating PTH actions in bone. Recently, we have developed a transgenic mouse model (CL), in which a constitutively active human PTH/PTHrP receptor was expressed under the control of the mouse alpha1 (I) collagen gene promoter. We will take advantage of this unique model to dissect out some of the mechanisms underlying the anabolic and catabolic actions of PTH in bone. By breeding CL mice with transgenic mice in which bone resorption is impaired by systemic overexpression of Osteoprotegerin (OPG), we will study whether bone resorption is a prerequisite for PTH/PTHrP receptor-induced bone formation (Specific Aim I). By comparing the phenotype of transgenic mice (OS) that express a constitutively active human PTH/PTHrP receptor under the control of the mouse osteocalcin gene promoter to the phenotype of CL animals, we will determine the role of the PTH/PTHrP receptor on osteoblasts/stromal cells of varying degrees of differentiation (Specific Aim II). By studying differentiation and activity of osteoprogenitor cells isolated from the bone marrow and the periosteum of CL mutant mice and then transplanted into immunodeficient mice, we will evaluate the role of the microenvironment in generating the different responsiveness of these cells to activation of the PTH/PTHrP receptor (Specific Aim III). By analyzing with microarray assays RNA extracted from osteoprogenitor cells and more mature osteoblasts isolated from both CL mutant mice and wild-type littermates, we will systematically study known and unknown genes that are regulated by activation of the PTH/PTHrP receptor in cells of the osteoblast lineage (Specific Aim IV).