OSTEOBLAST SPECIFIC ABLATION OF THE PTH/PTHRP RECEPTOR

描述：（摘自申请）：PTH/PTHrP 受体介导 甲状旁腺激素 (PTH) 和 PTH 相关蛋白 (PTHrP) 的作用 骨骼和其他器官。这种受体仅存在于骨骼中的细胞上 成骨细胞谱系，调节骨形成以及骨形成和作用 破骨细胞。持续施用 PTH 会导致净骨质流失。相比之下， 每日注射 1 次 PTH 可增加骨量。该项目寻求 了解 PTH 和 PTHrP 在骨骼中的多种作用，从而 建议最有效地利用 PTH/PTHrP 受体激活的策略 增加人的骨量。先前对小鼠的研究表明，消融 PTH/PTHrP 受体的异常导致骨骼结构和钙的异常 体内平衡。这些小鼠在出生时就会死亡；此外，消除受体 整个有机体使得无法区分直接和间接 对骨骼的影响。该项目解决了 PTH/PTHrP 的特定角色 骨细胞中的受体，通过专门去除 PTH/PTHrP 受体 成骨细胞谱系的细胞或来自生长板软骨细胞的细胞。在《目标一》中， cre-loxP 策略将用于生成具有 PTH/PTHrP 的小鼠品系 受体从成熟和不太成熟的细胞中特异性消除 成骨细胞谱系，仅来自成熟的成骨细胞，或来自生长晚期 软骨细胞。基因消融和变化的效率/特异性 将表征钙稳态。在目标 II 中，移除的效果 将评估 PTH/PTHrP 受体对成骨细胞功能的影响。之间的比较 该模型将揭示软骨细胞、未成熟软骨细胞的独特作用 成骨细胞样细胞和成骨细胞对骨反应的激活 PTH/PTHrP 受体。 PTHrP 通过 PTH/PTHrP 发挥作用的具体作用 受体，将通过在 PTH 无效背景中研究这些细胞系来确定。 在目标 III 中，将进行类似的研究以确定 PTH/PTHrP 受体刺激破骨细胞谱系的细胞。在目标 IV 中， 对成骨细胞谱系细胞群进行基因标记的策略 vivo 并随着时间的推移跟踪它们的命运将被用来确定 PTH/PTHrP 受体决定不同池之间的变化 成骨细胞前体、成骨细胞、衬里细胞和成骨细胞。

DESCRIPTION: (Taken from the application): The PTH/PTHrP receptor mediates the actions of both parathyroid hormone (PTH) and PTH-related protein (PTHrP) in bone and other organs. This receptor, found in bone only on cells of the osteoblast lineage, regulates bone formation and the formation and action of osteoclasts. PTH administered continuously causes net bone loss. In contrast, PTH administered by one daily injection increases bone mass. This project seeks to understand the multiple actions of PTH and PTHrP in bone and, thereby, to suggest strategies for most effectively using PTH/PTHrP receptor activation to increase bone mass in people. Previous studies in mice have shown that ablation of the PTH/PTHrP receptor leads to abnormalities in bone structure and calcium homeostasis. These mice die at birth; further, elimination of the receptor from the entire organism makes it impossible to distinguish direct from indirect effects on bone. This project addresses the specific roles of the PTH/PTHrP receptor in bone cells by removing the PTH/PTHrP receptor specifically from cells of the osteoblast lineage or from growth plate chondrocytes. In Aim I, the cre-loxP strategy will be used to generate mouse lines with the PTH/PTHrP receptor specifically ablated from both mature and less mature cells of the osteoblast lineage, from only mature osteoblasts, or from growth late chondrocytes. The efficiency/specificity of the gene ablations and changes in calcium homeostasis will be characterized. In Aim II, the effects of removing PTH/PTHrP receptors on osteoblast function will be assessed. Comparisons among the models will reveal the distinct roles of chondrocytes, immature osteoblast-like cells, and osteoblasts on bone responses to activation of the PTH/PTHrP receptor. The specific effects of PTHrP, acting through the PTH/PTHrP receptor, will be determined by studying these lines in a PTH null background. In Aim III, analogous studies will be performed to determine the role of the PTH/PTHrP receptor in stimulating cells of the osteoclast lineage. In Aim IV, a strategy for genetically marking cohorts of cells of the osteoblast lineage in vivo and following their fates over time will be used to determine the role of the PTH/PTHrP receptor in determining shifts between distinct pools of osteoblast precursors, osteoblasts, lining cells, and osteoblasts.