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:
- 金额:$ 20.59万
- 依托单位:
- 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:
- 关键词:AcidosisAnabolic AgentsAnabolismAnxietyApoptosisBenzodiazepinesBindingBone Marrow CellsBone ResorptionCatabolismCoculture TechniquesComplexContinuous InfusionCouplingCyclic AMPDataDinoprostoneEquilibriumFamilyFractureG-Protein-Coupled ReceptorsGPR68 geneGTP BindingGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGene ExpressionGoalsImmunoprecipitationImplantIn VitroInfusion proceduresKnockout MiceLactic acidLorazepamMediatingMetabolic Bone DiseasesModelingMolecularMusOsteoblastsOsteoclastsOsteogenesisOsteoporosisPTGS2 genePTH geneParathyroid Hormone ReceptorPathway interactionsProductionProtonsPublishingPumpReceptor SignalingScanningSignal PathwaySignal TransductionSleeplessnessSpecificityTNFSF11 geneTestingTherapeuticTherapeutic EffectToxic effectTreatment EfficacyWild Type Mousebasebonebone lossbone masscost effectivedesignextracellularin vivoinsightmembermicroCTmineralizationosteoblast differentiationpreventresponseskeletal
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.
项目总结/摘要
骨质疏松症是一种常见的代谢性骨骼疾病,是由于以下因素之间的平衡被破坏而导致的
成骨细胞骨形成和成骨细胞骨吸收。PTH的间歇给药增加骨
质量,而PTH的持续输注促进骨吸收。然而,
产生这种骨骼反应的不同信号通路仍然知之甚少。这是公认的
酸中毒抑制成骨细胞骨形成并增加骨细胞骨吸收。卵巢
癌G蛋白偶联受体1(OGR 1)是质子敏感GPCR家族的成员,
细胞外pH信号主要传递到骨中的Gq/PLC信号。已发表的研究和我们的初步数据
已经证明PTH受体和OGR 1促进合成代谢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如劳拉西泮
导致骨折。我们已经证明劳拉西泮作为OGR 1的Gq偏置变构调节剂,
以优先诱导Gq/PLC信号传导。这些发现表明劳拉西泮的使用
骨折可能归因于OGR 1偏置信号传导。我们的初步数据显示,
治疗促进乳酸产生并增加OGR 1表达,而舒拉西泮(另一种
苯二氮卓类)作为OGR 1的变构调节剂,使OGR 1信号偏向Gαs/cAMP
(治疗)途径。基于这些发现,我们假设OGR 1介导了
持续的PTH对骨的影响,而舒拉西泮可以偏置OGR 1信号传导,以“调节”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。目标1将确定是否
舒拉西泮在体内将持续的PTH分解代谢作用转化为骨增强作用。在目标2中,我们将描述
舒拉西泮通过促进偏置OGR 1信号传导逆转PTH分解代谢作用的机制
体外我们预测,舒拉西泮,而不是劳拉西泮转移的持续甲状旁腺激素向合成代谢
通过促进Gs-biased OGR 1信号传导对骨的影响。成功完成拟议的研究将不会
不仅促进了我们对PTH对骨的复杂影响的理解,而且还提供了靶向Gs的证据,
偏置的OGR 1信号传导可以使连续的PTH治疗向治疗效果转变。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bin Wang其他文献
Photodegradation of Dechlorane Plus in n-nonane under the irradiation of xenon lamp
氙灯照射下正壬烷中 DeChlorane Plus 的光降解
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Yang Yang;Gang Yu;Shubo Deng;Bin Wang - 通讯作者:
Bin Wang
Bin Wang的其他文献
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{{ truncateString('Bin Wang', 18)}}的其他基金
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通过新型干扰肽靶向 PTH1R 信号通路治疗骨关节炎
- 批准号:
10472490 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone
靶向泛素-蛋白酶体途径逆转 PTH 在骨中的分解代谢作用
- 批准号:
10656316 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
Targeting the PTH1R Signaling Pathway for Osteoarthritis Therapy by a Novel Disruptor Peptide
通过新型干扰肽靶向 PTH1R 信号通路治疗骨关节炎
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10667511 - 财政年份:2020
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$ 20.59万 - 项目类别:
Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone
靶向泛素-蛋白酶体途径逆转 PTH 在骨中的分解代谢作用
- 批准号:
10266824 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
Targeting the PTH1R Signaling Pathway for Osteoarthritis Therapy by a Novel Disruptor Peptide
通过新型干扰肽靶向 PTH1R 信号通路治疗骨关节炎
- 批准号:
10222574 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
Targeting the PTH1R Signaling Pathway for Osteoarthritis Therapy by a Novel Disruptor Peptide
通过新型干扰肽靶向 PTH1R 信号通路治疗骨关节炎
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10034154 - 财政年份:2020
- 资助金额:
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Coordination of DNA repair and transcription by ubiquitin modification at DNA double strand breaks
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10599965 - 财政年份:2020
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Coordination of DNA repair and transcription by ubiquitin modification at DNA double strand breaks
DNA 双链断裂处泛素修饰协调 DNA 修复和转录
- 批准号:
10380138 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
Targeting the ubiquitin-proteasome pathway to reverse catabolic action of PTH in bone
靶向泛素-蛋白酶体途径逆转 PTH 在骨中的分解代谢作用
- 批准号:
10450164 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 20.59万 - 项目类别:
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