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
基本信息
- 批准号:10472490
- 负责人:
- 金额:$ 33.98万
- 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:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AffinityAmino AcidsAnabolic AgentsAwardBindingBinding ProteinsBinding SitesBiochemicalCartilageCatabolismCellsChondrocytesClinical TrialsComplexCyclic AMPDataDegenerative polyarthritisDependovirusDevelopmentDisease ProgressionDoxycyclineEventGTP-Binding Protein alpha Subunits, GsGenetic MaterialsGoalsHumanHypertrophyInjectionsJointsKnee jointLesionMediatingMesenchymalModelingMusNF-kappa BNatural regenerationOutcomeOxidative StressPTH geneParathyroid Hormone ReceptorPathogenesisPathogenicityPathway interactionsPeptidesPlayPreventionProtein InhibitionPublishingReactive Oxygen SpeciesReceptor SignalingRegulationRoleSignal PathwaySignal TransductionTestingTherapeuticTherapeutic EffectToxic effectTropismWNT Signaling PathwayWorkarmarticular cartilagebasebeta catenincartilage degradationcartilage repaircost effectivedesignenzyme activityenzyme pathwayimprovedin vivomedication compliancemolecular modelingmouse modelnovelparathyroid hormone (1-34)parathyroid hormone-related proteinparticlepre-clinicalpreventprotective effectreceptorresponsetransgene delivery
项目摘要
Project Summary/Abstract
The long-term goal of this project is to design cost-effective anabolic agents with less toxicity, and convenient
use for the treatment of osteoarthritis (OA). Current treatments of OA have limited effects on the prevention
and progression of cartilage degeneration. Complex signaling events in cartilage underlie OA pathogenesis
and these can be targeted. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) bind
to the type I PTH/PTHrP receptor (PTH1R) to elicit both Gs/cAMP and Gq/PLC signaling pathways. Published
as well as our preliminary data demonstrate a PTH1R Gs/cAMP signaling arm that is therapeutic and a
Gq/PLC signaling arm that is pathogenic. Beta-catenin mediates canonical Wnt signaling, facilitates
chondrocyte hypertrophic differentiation and plays an important role in OA development. However, the
interplay between PTH1R and beta-catenin that contributes to OA pathogenesis remains poorly understood.
Recent data from others and our group have demonstrated that beta-catenin interacts with the PTH1R and
switches PTH1R signaling from Gs/cAMP to Gq/PLC activation. Moreover, beta-catenin expression is
increased in human OA, the outcome of which promotes the PTH1R signaling switch and causes articular
cartilage loss and OA development. It has been established that systemic or intra-articular administration of
PTH or PTHrP is able to prevent cartilage degeneration and regenerate the damaged cartilage. However, daily
injection of PTH or PTHrP is inconvenient and reduces medication adherence. PTHrP is normally secreted by
chondrocytes in low levels and is increased in OA. The carboxyl-terminal region of six amino acids is the beta-
catenin binding site in PTH1R. Our preliminary studies have determined that this six-amino-acid peptide
(disruptor peptide) blocks beta-catenin binding to PTH1R. Based on these findings, we hypothesize that the
disruptor peptide biases endogenous PTHrP-induced PTH1R signaling to favor the therapeutic signaling arm
and improve the ability of PTHrP to inhibit cartilage degeneration and treat/prevent OA. Three specific aims are
proposed to test this hypothesis. Aim 1 will develop a superior disruptor peptide (SDP) to efficiently block the
interaction of beta-catenin with PTH1R and inhibit the beta-catenin-mediated PTH1R signaling switch. In Aim
2, we will establish whether the adeno-associated virus expressing SDP prevents cartilage lesions and
increase cartilage repair in a mouse OA model. Aim 3 will characterize mechanisms by which the SDP
regulates PTHrP effects on chondrocyte hypertrophic differentiation and chondrocyte catabolism. Successful
completion of these studies therefore constitutes important preclinical findings that would facilitate
advancement of this work toward clinical trials of OA, and ultimate application in humans.
项目总结/摘要
本项目的长期目标是设计出具有低毒性、方便、经济的合成代谢药物,
用于治疗骨关节炎(OA)。目前的OA治疗方法对预防OA的作用有限,
和软骨退化的进展。软骨中的复杂信号事件是OA发病机制的基础
这些都是有针对性的。甲状旁腺激素(PTH)和甲状旁腺相关蛋白(PTHrP)结合
与I型PTH/PTHrP受体(PTH1R)结合以引发Gs/cAMP和Gq/PLC信号传导途径。发表
以及我们的初步数据表明,PTH1R Gs/cAMP信号臂是治疗性的,
Gq/PLC信号臂是致病的。β-连环蛋白介导经典Wnt信号传导,促进
软骨细胞肥大分化,并在OA发展中起重要作用。但
PTH1R和β-连环蛋白之间的相互作用对OA发病机制的影响仍然知之甚少。
来自其他人和我们小组的最新数据表明,β-连环蛋白与PTH1R相互作用,
将PTH1R信号从Gs/cAMP转换为Gq/PLC激活。此外,β-连环蛋白表达是
增加人类OA,其结果促进PTH1R信号转导开关,并导致关节炎。
软骨损失和OA发展。已经确定,全身或关节内施用
PTH或PTHrP能够防止软骨退化并再生受损的软骨。然而,每天
注射PTH或PTHrP是不方便的,并降低了药物的依从性。PTHrP通常由
软骨细胞中的低水平和增加OA。六个氨基酸的羧基末端区域是β-
PTH1R中的连环蛋白结合位点。我们的初步研究已经确定这种六氨基酸肽
(破坏肽)阻断β-连环蛋白与PTH1R的结合。基于这些发现,我们假设
干扰肽使内源性PTHrP诱导的PTH1R信号偏向于治疗信号臂
并提高PTHrP抑制软骨退变和治疗/预防OA的能力。三个具体目标是
来检验这个假设。目的1将开发一种上级干扰肽(SDP),
β-连环蛋白与PTH1R相互作用,抑制β-连环蛋白介导的PTH1R信号转导开关。在aim中
2,我们将确定表达SDP的腺相关病毒是否能预防软骨损伤,
增加小鼠OA模型中软骨修复。目标3将描述SDP
调节PTHrP对软骨细胞肥大分化和软骨细胞增殖的作用。成功
因此,这些研究的完成构成了重要的临床前发现,
推进这项工作的临床试验OA,并最终应用于人类。
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
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:
$ 33.98万 - 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:
10667511 - 财政年份:2020
- 资助金额:
$ 33.98万 - 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:
$ 33.98万 - 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:
$ 33.98万 - 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:
9896526 - 财政年份:2020
- 资助金额:
$ 33.98万 - 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:
10034154 - 财政年份:2020
- 资助金额:
$ 33.98万 - 项目类别:
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:
10599965 - 财政年份:2020
- 资助金额:
$ 33.98万 - 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:
$ 33.98万 - 项目类别:
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:
$ 33.98万 - 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:
$ 33.98万 - 项目类别:
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