Biasing OGR1 signaling to optimizing PTH therapeutic effect

偏向 OGR1 信号传导以优化 PTH 治疗效果

基本信息

批准号：
9896526
负责人：
Bin Wang
金额：
$ 20.59万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896526
关键词：
Acidosis Anabolic Agents Anabolism Anxiety Apoptosis Benzodiazepines Binding Bone Marrow Cells Bone Resorption Catabolism Coculture Techniques Complex Continuous Infusion Coupling Cyclic AMP Data Dinoprostone Equilibrium Family Fracture G-Protein-Coupled Receptors GPR68 gene GTP Binding GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gene Expression Goals Immunoprecipitation Implant In Vitro Infusion procedures Knockout Mice Lactic acid Lorazepam Mediating Metabolic Bone Diseases Modeling Molecular Mus Osteoblasts Osteoclasts Osteogenesis Osteoporosis PTGS2 gene PTH gene Parathyroid Hormone Receptor Pathway interactions Production Protons Publishing Pump Receptor Signaling Scanning Signal Pathway Signal Transduction Sleeplessness Specificity TNFSF11 gene Testing Therapeutic Therapeutic Effect Toxic effect Treatment Efficacy Wild Type Mouse base bone bone loss bone mass cost effective design extracellular in vivo insight member microCT mineralization osteoblast differentiation prevent response skeletal

项目摘要

Project Summary/Abstract Osteoporosis is a common metabolic bone disease and results from a disruption of the balance between osteoblastic bone formation and osteoclastic bone resorption. Intermittent administration of PTH increases bone mass, whereas continuous infusion of PTH promotes bone resorption. However, the mechanisms underlying the distinct signaling pathways that generate this skeletal response remain poorly understood. It is well accepted that acidosis suppresses osteoblastic bone formation and augments osteoclastic bone resorption. Ovarian cancer G protein-coupled receptor 1 (OGR1), a member of the proton sensing GPCR family, transduces extracellular pH signals primarily into Gq/PLC signaling in bone. Both published studies and our preliminary data have demonstrated PTH receptor and OGR1 promote a concomitant activation of anabolic Gαs/cAMP and catabolic Gαq/PLC signaling pathways. It has been observed that some benzodiazepines such as lorazepam cause bone fractures. We have demonstrated that lorazepam acts as a Gq-biased allosteric modulator of OGR1 to preferentially induce Gq/PLC signaling. These findings suggest that the association between lorazepam use and bone fracture may be ascribed to OGR1 biased signaling. Our preliminary data show that continuous PTH treatment promotes lactic acid production and increases OGR1 expression, and that sulazepam (another benzodiazepine) acts as an allosteric modulator of OGR1 to bias OGR1 signaling toward the Gαs/cAMP (therapeutic) pathway. Based on these findings, we hypothesize that OGR1 mediates the catabolic effect of continuous PTH on bone, and sulazepam can bias OGR1 signaling to “tune” PTH receptor signaling toward its therapeutic pathway. Two specific aims are proposed to test this hypothesis. Aim 1 will establish whether sulazepam converts continuous PTH catabolic effect to bone anabolism in vivo. In Aim 2, we will characterize the mechanisms by which sulazepam reverses the catabolic effect of PTH by promoting biased OGR1 signaling in vitro. We predict that sulazepam but not lorazepam shifts the catabolism of continuous PTH toward an anabolic effect on bone by promoting Gs-biased OGR1 signaling. Successful completion of the proposed studies will not only advance our understanding complex effects of PTH on bone, but also provide evidence that targeting Gs- biased OGR1 signaling can shift continuous PTH treatment toward to therapeutic effect.

项目摘要/摘要骨质疏松症是一种常见的代谢骨病，是由于破坏成骨细胞骨形成和整骨骨骨分辨率。间歇性施用PTH会增加骨骼质量，而连续输注PTH会促进骨骼分辨率。但是，产生这种骨骼反应的独特信号通路仍然了解得很糟糕。这是公认的酸中毒会抑制成骨细胞骨形成并增强整骨骨的分辨率。卵巢癌G蛋白偶联受体1（OGR1）是质子传感GPCR家族的成员，可转导细胞外pH信号主要到骨中的GQ/PLC信号传导。既发表的研究又是我们的初步数据已经证明了PTH受体和OGR1促进了合成代谢GαS/CAMP的同时激活分解代谢GαQ/PLC信号通路。已经观察到一些苯二氮卓类药物，例如劳拉西me 引起骨折。我们已经证明，Lorazepam充当OGR1的GQ偏置变构调节剂优先诱导GQ/PLC信号传导。这些发现表明Lorazepam使用之间的关联骨断裂可以分配给OGR1偏置信号传导。我们的初步数据表明连续PTH 治疗促进乳酸的产生并增加OGR1的表达，而Surazepam（另一种苯二氮卓）充当OGR1的变构调节剂，偏向OGR1信号传导朝GαS/CAMP偏向（治疗）途径。基于这些发现，我们假设OGR1介导骨头上的连续PTH和Sulazepam可以使OGR1信号传导偏向“调谐” PTH受体信号传导治疗途径。提出了两个具体目标来检验这一假设。 AIM 1将确定是否是否 Sulazepam将连续的PTH分解代谢作用转化为体内骨合成代谢。在AIM 2中，我们将描述 Surazepam通过促进有偏见的OGR1信号传导逆转PTH的分解代谢作用的机制体外。我们预测Surazepam而不是Lorazepam将连续PTH的分解代谢转移到合成代谢通过促进GS偏置的OGR1信号传导对骨骼的影响。成功完成拟议的研究将不会只能促进我们理解PTH对骨骼的复杂影响，但也提供了靶向GS-的证据偏置的OGR1信号传导可以将连续的PTH处理转移到治疗效果。