Mechanisms of TMJ development and long-term function

颞下颌关节发育和长期功能的机制

基本信息

  • 批准号:
    8614830
  • 负责人:
  • 金额:
    $ 42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The temporomandibular joint (TMJ) is different from other synovial joints, in that it contains an articular disc that separates the joint space into tw synovial cavities. These distinctive features enable complex anatomical rearrangements of TMJ that take place during mastication and speech. These movements also impart shearing and frictional loads and a near dislocation of the joint. To protect joint integrity from destructive mechanical friction, superficial and disc cells produce boundary lubricants including hyaluronic acid (HA) and lubricin. Thus, deterioration of joint lubrication with age or by other insults may underlie disc adhesion and degenerative TMJ disorders. We propose to study currently poorly understood developmental aspects of TMJ biology that are critically important for TMJ functions and its long-term health. Our preliminary data showed that a secreted signaling factor, Indian hedgehog (Ihh), plays pivotal roles in TMJ development. Global Ihh ablation led to a failure of disc and synovial cavity formation, and loss of TGF-β1, PTHrP and lubricin expression. Postnatal ablation of Ihh caused markedly reduced lubricin expression and disc adhesions. These findings led to our central hypothesis that Ihh signaling is required for both TMJ formation and postnatal function. In Aim 1, the roles of Ihh signaling in TMJ development will be further defined. Initially, we will relate the spatio-temporal patterns of Ihh signaling (Gli1 activation) o the expression of hedgehog receptors, signal transducers and phenotype defining genes during TMJ development. We will then use loss and gain of function approaches to delete Smoothened or Patched1 in TMJ cells at critical developmental stages. In Aim 2, we will test the hypothesis that TGF-β1 and PTHrP mediate Ihh action on its target cells in TMJ by asking whether TGF-β1 and/or PTHrP are sufficient to rescue Ihh-null TMJ phenotype and whether conditional deletion of these genes in TMJ produce defects similar to those seen in Ihh-null mice. We will further delineate Ihh-TGF-β and Ihh- PTHrP signaling pathways and their potential interactions in the regulation of joint lubricant production and development of relevant cell types. In Aim 3, we will study the roles of joint lubricants in the Ihh- dependent postnatal TMJ maintenance. Respective roles of HA and lubricin in the protection of the TMJ will be determined by analyzing lubricin (Prg4)-null and conditional HA synthase 2 (HAS2)-deficient mice. We will also test whether TMJ defects in Ihh-null mice can be rescued by systemic or local injection of a hedgehog agonist, PTHrP/PTH, TGF-β1 or local delivery of lubricin- and/or HAS2-expression vectors. In sum, this project will provide novel, important and far-reaching information on hedgehog signaling in TMJ formation and maintenance. Our rescue experiments should provide a proof-of-principle that TMJ defects, including disc adhesions, are amenable to therapeutic intervention.
描述(由申请人证明):颞叶关节(TMJ)与在咀嚼和言语中分开的关节空间不同机械摩擦,表面和圆盘细胞的亮脑剂在内,包括年龄的关节酸或其他Inderlie Disc aDhescasc和退化性TMJ疾病刺猬(IHH)在TMJ发育中起着关键作用,PTHRP和润滑性表达。 IHHHHHHH在TMJ开发中的E角色将进一步定义,我们将与IHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH的作用(GLI1激活)联系起来。阶段。 TMJ会产生SIHH-null小鼠。 - 依赖性后TMJ。 ,TGF-β1或润滑剂和/或HAS2表达载体的局部涂料。

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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EIKI KOYAMA其他文献

EIKI KOYAMA的其他文献

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{{ truncateString('EIKI KOYAMA', 18)}}的其他基金

Evaluation of Prg4 as a New Therapy for TMJ Disc Degeneration
Prg4 作为 TMJ 椎间盘退变新疗法的评估
  • 批准号:
    10525000
  • 财政年份:
    2022
  • 资助金额:
    $ 42万
  • 项目类别:
Evaluation of Prg4 as a New Therapy for TMJ Disc Degeneration
Prg4 作为 TMJ 椎间盘退变新疗法的评估
  • 批准号:
    10677033
  • 财政年份:
    2022
  • 资助金额:
    $ 42万
  • 项目类别:
Mechanical Regulation of Cell Fate and Multi-Scale Function in the Developing Meniscus
半月板发育中细胞命运和多尺度功能的机械调节
  • 批准号:
    10359683
  • 财政年份:
    2019
  • 资助金额:
    $ 42万
  • 项目类别:
Mechanical Regulation of Cell Fate and Multi-Scale Function in the Developing Meniscus
半月板发育中细胞命运和多尺度功能的机械调节
  • 批准号:
    9903234
  • 财政年份:
    2019
  • 资助金额:
    $ 42万
  • 项目类别:
Mechanical Regulation of Cell Fate and Multi-Scale Function in the Developing Meniscus
半月板发育中细胞命运和多尺度功能的机械调节
  • 批准号:
    10589080
  • 财政年份:
    2019
  • 资助金额:
    $ 42万
  • 项目类别:
Mechanical Regulation of Cell Fate and Multi-Scale Function in the Developing Meniscus
半月板发育中细胞命运和多尺度功能的机械调节
  • 批准号:
    9764868
  • 财政年份:
    2019
  • 资助金额:
    $ 42万
  • 项目类别:
Mechanisms of TMJ development and long-term function
颞下颌关节发育和长期功能的机制
  • 批准号:
    8887326
  • 财政年份:
    2014
  • 资助金额:
    $ 42万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    8475565
  • 财政年份:
    2011
  • 资助金额:
    $ 42万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    8294622
  • 财政年份:
    2011
  • 资助金额:
    $ 42万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    8183318
  • 财政年份:
    2011
  • 资助金额:
    $ 42万
  • 项目类别:

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骨唾液酸蛋白在调节牙周发育和修复中的作用
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