Biasing OGR1 signaling to optimizing PTH therapeutic effect

偏向 OGR1 信号传导以优化 PTH 治疗效果

• 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
• 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

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性骨骼疾病，是由于 成骨细胞性骨形成和破骨细胞性骨吸收。间歇性服用甲状旁腺素可增加骨骼 持续输注甲状旁腺素可促进骨吸收。然而，潜在的机制是 产生这种骨骼反应的不同信号通路仍然知之甚少。它被广泛接受 酸中毒抑制成骨细胞骨形成，增加破骨细胞骨吸收。卵巢 癌症G蛋白偶联受体1(OGR1)是质子感受性GPCR家族的一员，是一种信号转导分子 细胞外pH信号主要进入骨骼中的GQ/PLC信号。发表的研究和我们的初步数据 已证实甲状旁腺素受体和OGR1促进合成代谢GαS/cAMP的伴随激活和 分解代谢的G-αQ/PLC信号通路。已经观察到一些苯二氮类药物，如劳拉西潘 导致骨折。我们已经证明劳拉西潘是OGR1的Gq偏置的变构调节剂 优先诱导GQ/PLC信号转导。这些发现表明劳拉西潘的使用与 骨折可能归因于OGR1偏向的信号转导。我们的初步数据显示，持续的PTH 治疗促进乳酸的产生并增加OGR1的表达，而舒拉西潘(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，我们假设OGR1介导的分解代谢作用 骨骼上持续的甲状旁腺激素，而舒拉西潘可以偏向OGR1信号，使甲状旁腺激素受体信号向其“调谐” 治疗路径。为了检验这一假说，本文提出了两个具体目标。目标1将确定 舒拉西潘在体内将持续的甲状旁腺素分解代谢作用转化为骨合成代谢作用。在目标2中，我们将描述 舒拉西潘通过促进偏向OGR1信号转导逆转甲状旁腺素分解代谢作用的机制 在试管中。我们预测，舒拉西潘而不是劳拉西潘将持续性甲状旁腺素的分解代谢转化为合成代谢。 促进Gs偏向的OGR1信号对骨骼的影响。成功完成建议的研究将不会 这不仅加深了我们对甲状旁腺激素对骨的复杂影响的理解，而且也为靶向Gs- 有偏向的OGR1信号可以使持续的甲状旁腺激素治疗转向治疗效果。