OSTEOBLAST SPECIFIC ABLATION OF THE PTH/PTHRP RECEPTOR

描述：(摘自申请)：甲状旁腺素/甲状旁腺素受体介导 甲状旁腺激素(PTH)及其相关蛋白(PTHrP)在心肌梗死中的作用 骨头和其他器官。这种受体只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。持续服用甲状旁腺激素会导致净骨质丢失。相比之下， 每天注射一次甲状旁腺素会增加骨量。这个项目寻求 了解甲状旁腺激素和甲状旁腺激素受体在骨骼中的多重作用，从而 建议最有效地利用PTH/PTHrP受体激活的策略 增加人体的骨量。此前在小鼠身上的研究表明，消融 甲状旁腺激素/甲状旁腺素受体缺失导致骨结构和钙的异常 动态平衡。这些小鼠在出生时就会死亡；此外，从 整个生物体不可能区分直接和间接 对骨骼的影响。该项目涉及PTH/PTHrP的具体作用 通过特异性去除甲状旁腺激素/甲状旁腺素受体在骨细胞中的受体 成骨细胞谱系的细胞或来自生长板软骨细胞。在AIM I中， Cre-loxP策略将用于产生带有PTH/PTHrP的小鼠系 从成熟和不成熟的细胞中特异性地消融的受体 成骨细胞谱系，仅来自成熟的成骨细胞，或来自生长后期 软骨细胞。基因消融的效率/特异度和 钙稳态的特征将被描述。在AIM II中，消除 将评估PTH/PTHrP受体对成骨细胞功能的影响。比较以下几项 这些模型将揭示未成熟软骨细胞的不同作用 成骨细胞样细胞和成骨细胞对骨激活的反应 甲状旁腺素/甲状旁腺素受体。甲状旁腺素rP通过甲状旁腺素/甲状旁腺素rP的特异性作用 受体，将通过在PTH零背景下研究这些线来确定。 在目标三中，将进行类似的研究，以确定 PTH/PTHrP受体在刺激破骨细胞系细胞中的作用在目标四中，一个 对成骨细胞系的细胞队列进行遗传标记的策略 活体和随时间推移的命运将被用来确定 甲状旁腺激素/甲状旁腺素受体在决定不同脑区间移位中的作用 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.