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：
EIKI KOYAMA
金额：
$ 42万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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

来源：
https://reporter.nih.gov/project-details/8614830
关键词：
Ablation Adhesions Age Agonist Apical Area Biology Cells Complex Cues DNA Sequence Rearrangement Data Defect Deterioration Development Embryo Erinaceidae Failure Fossa Friction Future Gene Deletion Genes Health Hyaluronic Acid Injection of therapeutic agent Joint Dislocation Joints Knockout Mice Lead Limb structure Lubricants Lubrication Maintenance Mastication Mechanics Mediating Movement Mus Mutant Strains Mice Pathway interactions Pattern Phenotype Play Production Quality of life Receptor Signaling Recombinant Proteins Recombinants Regulation Relative (related person)Reporter Role Severities Signal Pathway Signal Transduction Speech Staging Structure Sum Surface Synovial Fluid Temporomandibular Joint Temporomandibular Joint Disorders Testing Therapeutic Therapeutic Intervention Time Transducers Up-Regulation cell type expression vector gain of function human SMO protein joint function loss of function lubricin mutant novel parathyroid hormone-related protein postnatal receptor research study skeletogenesis smoothened signaling pathway transcription factor

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（由申请人提供）：颞下颌关节 (TMJ) 与其他滑液关节不同，因为它包含将关节空间分隔成两个滑液腔的关节盘，这些独特的特征使得 TMJ 能够在运动过程中发生复杂的解剖学重新排列。这些运动还会产生剪切力和摩擦力，并导致关节近乎脱位。为了保护关节完整性，避免破坏性机械摩擦，表面细胞和椎间盘细胞会产生损伤。因此，随着年龄的增长或其他损伤，关节润滑的恶化可能是椎间盘粘连和退行性颞下颌关节紊乱的基础，我们建议研究目前对颞下颌关节生物学至关重要的了解甚少的发育方面。我们的初步数据表明，印度刺猬 (Ihh) 分泌信号因子在 TMJ Global Ihh 发育中发挥着关键作用。消融导致椎间盘和滑膜腔形成失败，并且 Ihh 的出生后消融导致 lubricin 表达和椎间盘粘连显着减少。在目标 1 中，我们将进一步定义 Ihh 信号在 TMJ 发育中的作用。然后，我们将使用功能丧失和获得的方法在关键发育阶段删除 TMJ 细胞中的 Smoothened 或 Patched1。 2，我们将通过询问 TGF-β1 和/或 PTHrP 是否足以拯救 Ihh-null TMJ 表型，以及 TMJ 中这些基因的条件性删除是否会产生与 Ihh-null 小鼠中观察到的缺陷相似的缺陷。我们将进一步描述 Ihh-TGF-β 和 Ihh-PTHrP 信号通路及其在调节中的潜在相互作用。关节润滑剂的产生和相关细胞类型的发育在目标 3 中，我们将研究关节润滑剂在 Ihh 依赖性产后 TMJ 维持中的作用。 lubricin 对 TMJ 的保护作用将通过分析 lubricin (Prg4) 缺失和条件性 HA 合酶 2 (HAS2) 缺陷小鼠来确定。我们还将测试是否可以通过全身或局部注射来挽救 Ihh 缺失小鼠的 TMJ 缺陷。 Hedgehog 激动剂、PTHrP/PTH、TGF-β1 或润滑素和/或 HAS2 表达载体的局部递送。总之，该项目将提供有关 TMJ 形成和维护中刺猬信号的新颖、重要且影响深远的信息，我们的救援实验应该提供原理证明，证明 TMJ 缺陷（包括椎间盘粘连）适合治疗干预。