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Novel Regulation of PTH Receptor Functions in Bone

骨中 PTH 受体功能的新调控

基本信息

批准号：
8844211
负责人：
Bin Wang
金额：
$ 7.75万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8844211
关键词：
Adenylate Cyclase Anabolism Animals Binding Bone Density Bone Resorption Bone remodeling Cells Clinical Co-Immunoprecipitations Continuous Infusion Cyclic AMP Data Disease Down-Regulation End stage renal failure Exposure to Functional disorder G-Protein-Coupled Receptors Goals Herpes zoster disease Homeostasis Hyperparathyroidism Knockout Mice Knowledge Ligands Measures Mediating Minerals Mus Opiates Opioid Receptor Osteoblasts Osteogenesis Osteoporosis PDZ protein PTEN protein Parathyroid Hormone Receptor Pathway interactions Patients Phospholipase C Phosphotransferases Proteins Proteomics Proto-Oncogene Proteins c-akt Receptor Down-Regulation Recycling Regulation Renal Osteodystrophy Research Resistance Role Scaffolding Protein Scanning Secondary Hyperparathyroidism Signal Pathway Signal Transduction Techniques Testing Therapeutic Therapeutic Effect Wild Type Mouse base bone bone loss bone mass bone metabolism design human RGS2 protein human RIPK1 protein insight knock-down member membrane-associated guanylate kinase novel parathyroid hormone (1-34)presynaptic density protein 95 public health relevance receptor receptor function research study response skeletal small hairpin RNA spinophilin tomography trafficking

项目摘要

DESCRIPTION (provided by applicant): The type 1 parathyroid hormone receptor (PTH1R), a member of G-protein coupled receptors (GPCRs), mediates PTH actions to maintain bone mineral homeostasis. Osteoblast dysfunction leading to bone loss is thought to be a key mechanism in osteoporosis. Intermittent administration of PTH (1-34) stimulates bone formation in patients and in experimental animals. Continuous infusion of PTH (1-34), which mimics pathological changes in clinical hyperparathyroidism, causes bone resorption. Patient with end-stage renal disease develops a systemic disorder of mineral and bone metabolism, such as renal osteodystrophy. PTH1R down-regulation and skeletal resistance to PTH not only reduce the therapeutic effect of PTH treatment for osteoporosis, but also occur in diseases including secondary hyperparathyroidism and renal osteodystrophy. To protect against the PTH1R down-regulation is a complementary strategy that may be useful for treatment of these diseases. Although the signaling pathways of PTH receptor are reasonably well understood, the mechanism of regulation of PTH1R functions remains to be characterized. Postsynaptic density 95/discs large/zona occludens (PDZ) scaffolding proteins comprise a key class of GPCRs-interacting proteins that can strongly influence signaling and trafficking of GPCRs. We identified two novel PTH1R associating proteins by using a newly developed proteomic array of distinct PDZ domains and coimmunoprecipitation experiments. These PDZ scaffolding proteins, MAGI-3 and spinophilin, are endogenously expressed in osteoblasts. Both MAGI-3 and spinophilin increase PTH-induced cAMP formation in osteoblasts. Based on these observations, we hypothesize that MAGI-3 and spinophilin modulate PTH1R functions and protect against receptor down-regulation in bone. Three specific aims are developed to test this hypothesis. Aim 1 will determine the effects of MAGI-3 and spinophilin on PTH1R signaling in osteoblasts. In Aim 2, we will identify whether MAGI-3 and spinophilin protect against PTH1R down-regulation in osteoblasts. Aim 3 will define the role of spinophilin on bone formation bone resorption in mice treated with intermittent PTH. Successful completion of the proposed studies will provide novel and important information on the regulation of PTH1R signaling, trafficking, and functions by MAGI-3 and spinophilin in bone. The knowledge gained from these studies will provide important insight into therapeutics for the treatment of osteoporosis and other diseases related to PTH1R down-regulation such as secondary hyperparathyroidism and renal osteodystrophy.

描述（由申请人提供）：1型甲状旁腺激素受体（PTH 1 R）是G蛋白偶联受体（GPCR）的成员，介导PTH作用以维持骨矿物质稳态。成骨细胞功能障碍导致骨丢失被认为是骨质疏松症的关键机制。PTH（1-34）的间歇给药刺激患者和实验动物的骨形成。持续输注PTH（1-34），模拟临床甲状旁腺功能亢进的病理变化，导致骨吸收。终末期肾病患者发生全身性矿物质和骨代谢紊乱，如肾性骨营养不良。PTH 1 R下调和骨骼对PTH的抵抗不仅降低了PTH治疗骨质疏松症的疗效，而且还发生在包括继发性甲状旁腺功能亢进和肾性骨营养不良在内的疾病中。防止PTH 1 R下调是一种补充策略，可能有助于治疗这些疾病。虽然PTH受体的信号转导通路已被合理地理解，但PTH 1 R功能的调节机制仍有待表征。突触后密度95/盘大/闭锁（PDZ）支架蛋白包括一类关键的GPCR相互作用蛋白，可以强烈影响GPCR的信号传导和运输。我们确定了两个新的PTH 1 R相关蛋白，通过使用新开发的蛋白质组阵列的不同PDZ域和免疫共沉淀实验。这些PDZ支架蛋白，MAGI-3和亲棘蛋白，在成骨细胞中内源性表达。MAGI-3和spinophilin都增加成骨细胞中PTH诱导的cAMP形成。基于这些观察结果，我们假设MAGI-3和亲棘素调节PTH 1 R功能并防止骨中受体下调。三个具体的目标来测试这一假设。目的1研究MAGI-3和spinophilin对成骨细胞PTH 1 R信号转导的影响。在目标2中，我们将确定MAGI-3和spinophilin是否可以防止成骨细胞中PTH 1 R的下调。目的3：探讨嗜棘素对间歇性甲状旁腺激素治疗小鼠骨形成和骨吸收的影响。成功完成拟议的研究将提供新的和重要的信息PTH 1 R信号的调节，贩运和功能的MAGI-3和spinophilin在骨。从这些研究中获得的知识将为骨质疏松症和其他与PTH 1 R下调相关的疾病（如继发性甲状旁腺功能亢进和肾性骨营养不良）的治疗提供重要的见解。