FUNCTIONS OF PTH/PTHRP RECEPTOR, PTHRP AND PTH IN VIVO

PTH/PTHRP 受体、PTHRP 和 PTH 体内的功能

• 批准号: 6395868
• 负责人: HENRY M. KRONENBERG
• 金额: $ 17.51万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6395868
• 关键词: biological signal transduction; bone development; bone morphogenetic proteins; calcium metabolism; chondrocytes; developmental genetics; embryo /fetus; epiphysis; gene targeting; genetically modified animals; hormone receptor; hormone regulation /control mechanism; laboratory mouse; osteoblasts; osteoclasts; osteogenesis; parathyroid hormone related protein; parathyroid hormones

Description: (Taken directly from the application) Parathyroid hormone (PTH), a hormone, and parathyroid hormone-related protein (PTHrP), a paracrine factor, help regulate both bone growth and calcium homeostasis through interactions with a common PTH/PTHrP receptor. This signaling system interacts with other signaling systems including those triggered by Indian hedgehog (Ihh), bone morphogenic proteins (BMPs), and cytokines that activate gp130 to assure normal growth and calcium regulation. Genetically altered mice, including chimeric mice of mixed genetic lineage, will be used to understand the interactions of these signaling systems in vivo. Aim 1 will study regulation of the growth plate by PTHrP and Ihh through the use of chimeric mice. The role of a feedback loop between PTHrP and Ihh signaling in controlling the rate of chondrocyte differentiation will be assessed, and the role of Ihh in regulating differentiation of adjacent bone cells will be studied. The interactions of BMPs and PTHrP will be analyzed through matings that involve mice transgenic for expression of a constitutively active BMP receptor 1A. The effect of deleting the PTHrP gene from these mice will be analyzed. The lineage relationships of chondrocytes and osteoblasts will be analyzed by studying the fates of genetically marked chondrocytes in chimeric mice. Aim 2 will analyze the prenatal function of PTH through the study of PTH (-/-) mice. The distinct roles of PTH, PTHrP, and the PTH/PTHrP receptor in bone growth and calcium homeostasis will be analyzed by appropriate matings, followed by analyses of bone structure and parameters of calcium homeostasis. Aim 3 will study the interactions between PTH/PTHrP receptor signaling and gp130 signaling in stimulating osteoblast lineage cells, which then activate osteoclastogenesis and osteoclast action. Calcium homeostasis will be studied prenatally in gp130 (-/-) mice. The interactions between PTH and gp130 signaling will be studied in chimeric mice and in cell mixing experiments. Together, these studies will define the relationships of important signaling pathways in regulating normal bone development and calcium homeostasis in vivo.

描述：（直接摘自应用程序）甲状旁腺激素 (PTH)（一种激素）和甲状旁腺激素相关蛋白 (PTHrP)（一种旁分泌因子）通过与常见的 PTH/PTHrP 受体相互作用，帮助调节骨骼生长和钙稳态。该信号系统与其他信号系统相互作用，包括由印度刺猬 (Ihh)、骨形态发生蛋白 (BMP) 和激活 gp130 的细胞因子触发的信号系统，以确保正常生长和钙调节。基因改造的小鼠，包括混合遗传谱系的嵌合小鼠，将用于了解这些信号系统在体内的相互作用。目标 1 将通过使用嵌合小鼠研究 PTHrP 和 Ihh 对生长板的调节。将评估 PTHrP 和 Ihh 信号传导之间的反馈回路在控制软骨细胞分化速率中的作用，并将研究 Ihh 在调节相邻骨细胞分化中的作用。 BMP 和 PTHrP 的相互作用将通过交配进行分析，其中涉及表达组成型活性 BMP 受体 1A 的转基因小鼠。将分析从这些小鼠中删除 PTHrP 基因的效果。通过研究嵌合小鼠中基因标记的软骨细胞的命运，可以分析软骨细胞和成骨细胞的谱系关系。目标2将通过PTH (-/-)小鼠的研究来分析PTH的产前功能。将通过适当的交配来分析 PTH、PTHrP 和 PTH/PTHrP 受体在骨骼生长和钙稳态中的不同作用，然后分析骨骼结构和钙稳态参数。目标 3 将研究 PTH/PTHrP 受体信号传导与 gp130 信号传导在刺激成骨细胞谱系细胞中的相互作用，从而激活破骨细胞生成和破骨细胞作用。将在 gp130 (-/-) 小鼠中进行产前研究。 PTH 和 gp130 信号传导之间的相互作用将在嵌合小鼠和细胞混合实验中进行研究。这些研究将共同​​确定调节正常骨骼发育和体内钙稳态的重要信号通路的关系。