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:
    10034154
  • 负责人:
  • 金额:
    $ 34.32万
  • 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

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/文摘

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(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

Bin Wang的其他文献

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{{ truncateString('Bin Wang', 18)}}的其他基金

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:
    10472490
  • 财政年份:
    2020
  • 资助金额:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 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:
    $ 34.32万
  • 项目类别:

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