OSTEOBLAST SPECIFIC ABLATION OF THE PTH/PTHRP RECEPTOR

PTH/PTHRP 受体的成骨细胞特异性消融

• 批准号: 6660896
• 负责人: HENRY M. KRONENBERG
• 金额: $ 28.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6660896
• 关键词: 1,25 dihydroxycholecalciferol; bone density; bone development; bone metabolism; calcium metabolism; cell differentiation; chondrocytes; genetically modified animals; histology; hormone receptor; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; osteoblasts; osteoclasts; osteoporosis; parathyroid hormone related protein; parathyroid hormones; receptor expression; terminal nick end labeling

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.

描述：（摘自应用程序）：PTH/PTHrP受体介导 甲状旁腺激素（PTH）和PTH相关蛋白（PTHrP）在 骨头和其他器官。这种受体，只存在于骨骼中， 成骨细胞谱系，调节骨形成和骨形成的形成和行动， 破骨细胞持续给予PTH会导致净骨丢失。与此相反， 每天注射一次PTH可增加骨量。项目的目标是 了解PTH和PTHrP在骨中的多种作用，从而， 提出了最有效地利用PTH/PTHrP受体激活策略， 增加人的骨量。先前在小鼠身上的研究表明， PTH/PTHrP受体的异常导致骨结构和钙的异常 体内平衡这些小鼠在出生时死亡;此外，受体从 整个有机体使人无法区分直接和间接 对骨骼的影响本项目涉及PTH/PTHrP的具体作用 通过特异性去除骨细胞中的PTH/PTHrP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策略将用于产生具有PTH/PTHrP的小鼠系 受体特异性消融从成熟和不太成熟的细胞， 成骨细胞谱系，来自仅成熟的成骨细胞，或来自生长晚期的成骨细胞。 软骨细胞基因消融的效率/特异性和 将表征钙稳态。在目标二中， 将评估PTH/PTHrP受体对成骨细胞功能的影响。之间的比较 这些模型将揭示软骨细胞的不同作用， 成骨细胞样细胞和成骨细胞对骨反应的激活， PTH/PTHrP受体。通过PTH/PTHrP发挥作用的PTHrP的特异性作用 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受体在刺激破骨细胞谱系细胞中的作用在目标四中，a 用于遗传标记成骨细胞谱系细胞群的策略 体内和随着时间的推移，他们的命运将被用来确定的作用， PTH/PTHrP受体在确定不同库之间的变化中的作用 成骨细胞前体、成骨细胞、衬里细胞和成骨细胞。