Pathogenesis of Enthesopathy

附着点病变的发病机制

基本信息

  • 批准号:
    10474352
  • 负责人:
  • 金额:
    $ 35.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary Over half of sports injuries involve tendons and entheses, the insertion sites of tendons or ligaments to bones. A common enthesis disorder enthesophathy, representing one fourth of tendon diseases, results in a long-term disturbance of the load transfer and is a major cause of pain and disability. The exact pathogenesis of enthesopathy is largely unknown, and there is no effective disease modifying treatment for this disorder. The proposed project aims to elucidate the pathogenic mechanisms of enthesopathy and develop potential therapeutic solutions to prevent/treat this disease. Our preliminary studies suggest that TGFβ activation in bone tissue of the enthesis, in response to aberrant mechanical loading after enthesis injury, is an early change in the progression of enthesopathy. In a mouse model of enthesopathy, we observed upregulated TGFβ activity at the bone-fibrocartilage junction earlier, and entheses progressive degradation later after entheses injury. Moreover, transgenic mice with active TGFβ overexpression in bone recapitulated the enthesopathy phenotype, whereas the enthesopathy mice treated with a TGFβ neutralizing antibody had decelerated enthesis degeneration. To achieve bone-targeting delivery and slow release in bone tissue, we generated a new drug that conjugates a TGFβ inhibitor to Alendronate through a metabolically hydrolysable linker. The conjugate effectively inhibited TGFβ activity in bone in the active TGFβ transgenic mice. The central hypothesis of this study is that aberrant TGFβ activation at the bone-fibrocartilage junction initiates enthesopathy by recruiting stem/progenitor cells for blood vessel invasion and ossification in the fibrocartilage zone. To test this hypothesis, we will examine the role of elevated active TGFβ in the progression of enthesopathy using different mouse models (Aim 1). We will also determine the role of TGFβ-recruited stem/progenitor cells in the progression of enthesopathy using two genetic lineage tracing mice and an inducible tissue-specific TGFβ receptor-ablation mice (Aim 2). Finally, we will examine the therapeutic potential of the TGFβ inhibitor–Alendronate conjugate in enthesopathy (Aim 3). Results will provide evidence for clinical application of this conjugate as a therapy for enthesopathy.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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Xu Cao其他文献

Xu Cao的其他文献

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{{ truncateString('Xu Cao', 18)}}的其他基金

Sialylation of TLR2 Induces Osteoclast Fusion and Th 17 differentiation During Aging
TLR2 唾液酸化诱导衰老过程中破骨细胞融合和 Th 17 分化
  • 批准号:
    10430544
  • 财政年份:
    2022
  • 资助金额:
    $ 35.66万
  • 项目类别:
Sialylation of TLR2 Induces Osteoclast Fusion and Th 17 differentiation During Aging
TLR2 唾液酸化诱导衰老过程中破骨细胞融合和 Th 17 分化
  • 批准号:
    10650877
  • 财政年份:
    2022
  • 资助金额:
    $ 35.66万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10326800
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Endplate Sensory Innervations for LBP
LBP 的终板感觉神经支配
  • 批准号:
    10556415
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Endplate Sensory Innervations for LBP
LBP 的终板感觉神经支配
  • 批准号:
    10326802
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Skeleton and Joint Degeneration with Aging
骨骼和关节随衰老而退化
  • 批准号:
    10556410
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Endplate Sensory Innervations for LBP
LBP 的终板感觉神经支配
  • 批准号:
    10090196
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Skeleton and Joint Degeneration with Aging
骨骼和关节随衰老而退化
  • 批准号:
    10326799
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10556411
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Skeleton and Joint Degeneration with Aging
骨骼和关节随衰老而退化
  • 批准号:
    10090193
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:

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