CONSTITUTIVELY ACTIVE PTH/PTHRP RECEPTORS IN OSTEOBLAST

描述：（摘自应用程序）：PTH是一种重要的生理 骨转换和钙稳态的调节剂。尽管相当大的 尽管有大量的研究，但仍有许多未解答的问题， PTH在骨中的作用机制。体外和体内研究已经 证明了PTH/PTHrP受体在介导PTH 在骨头上的动作。最近，我们开发了一种转基因小鼠模型（CL）， 其中组成型活性的人PTH/PTHrP受体在 小鼠α 1（I）胶原基因启动子的控制。我们将利用 这一独特的模式，剖析出一些机制的基础上， PTH在骨中的合成代谢和分解代谢作用。通过将CL小鼠与 全身性过度表达损害骨吸收的转基因小鼠 骨保护素（OPG），我们将研究骨吸收是否是一个 PTH/PTHrP受体诱导骨形成的先决条件（特定目标I）。通过 比较组成型表达a的转基因小鼠（OS）的表型， 小鼠骨钙素基因调控下的活性人PTH/PTHrP受体 启动子的CL动物的表型，我们将确定的作用， 成骨细胞/基质细胞上的PTH/PTHrP受体不同程度地抑制成骨细胞/基质细胞的增殖。 具体目标二（Specific Aim II）通过研究细胞分化和活性， 从CL的骨髓和骨膜分离的骨祖细胞 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 这些细胞的PTH/PTHrP受体的活化（特异性目的III）。通过 用微阵列分析从骨祖细胞提取的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， 受成骨细胞中PTH/PTHrP受体活化的调节 具体目标IV（Specific Aim IV）。

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).