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：
10092958
负责人：
Bin Wang
金额：
$ 16.65万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092958
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.

项目概要/摘要骨质疏松症是一种常见的代谢性骨病，是由于骨与骨之间的平衡被破坏造成的。成骨细胞骨形成和破骨细胞骨吸收间歇性施用 PTH 可增加骨量。然而，持续输注 PTH 会促进骨吸收。产生这种骨骼反应的独特信号通路仍然知之甚少，但人们对此仍知之甚少。酸中毒抑制成骨细胞骨形成并增强破骨细胞骨吸收。癌症 G 蛋白偶联受体 1 (OGR1) 是质子感应 GPCR 家族的成员，可转导已发表的研究和我们的初步数据均将细胞外 pH 信号主要转化为骨中的 Gq/PLC 信号。已证明 PTH 受体和 OGR1 促进合成代谢 Gαs/cAMP 的同时激活，据观察，一些苯二氮卓类药物（例如劳拉西泮）会影响分解代谢 Gαq/PLC 信号通路。我们已经证明劳拉西泮可以作为 OGR1 的 Gq 偏向变构调节剂。优先诱导 Gq/PLC 信号传导这些发现表明劳拉西泮的使用之间存在关联。骨折可能归因于 OGR1 偏向信号传导。我们的初步数据表明，连续 PTH 存在。治疗可促进乳酸产生并增加 OGR1 表达，并且舒拉西泮（另一种苯二氮卓类）作为 OGR1 的变构调节剂，使 OGR1 信号偏向 Gαs/cAMP （治疗）途径基于这些发现，我们研究了 OGR1 介导的分解代谢作用。骨骼上有连续的 PTH，而舒拉西泮可以偏向 OGR1 信号传导，从而“调整”PTH 受体信号传导至其方向提出了两个具体目标来检验这一假设。舒拉西泮将持续的 PTH 分解代谢作用转化为体内骨合成代谢。舒拉西泮通过促进偏向 OGR1 信号传导逆转 PTH 分解代谢作用的机制我们预测，舒拉西泮（而不是劳拉西泮）会将连续 PTH 的分解代谢转变为合成代谢。通过促进 Gs 偏向的 OGR1 信号传导对骨骼的影响不会成功完成拟议的研究。不仅促进了我们对 PTH 对骨骼的复杂影响的理解，而且还提供了针对 Gs- 的证据偏向的 OGR1 信号传导可以使持续 PTH 治疗转向治疗效果。