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（由应用程序提供）：颞下颌关节（TMJ）与其他滑膜不同，因为它包含一个关节盘，将关节空间分离为TW滑膜。这些独特的特征使咀嚼和言语过程中发生的TMJ的复杂解剖重排。这些运动还赋予了剪切和摩擦载荷以及接头几乎脱位。为了保护关节完整性免受破坏性机械摩擦的影响，浅表和椎间盘细胞产生边界润滑剂，包括透明质酸（HA）和润滑剂。这是对年龄或其他侮辱的联合润滑的定义可能是椎间盘粘附和退化性TMJ疾病的基础。我们建议研究目前了解TMJ生物学的发展方面，这些方面对TMJ功能及其长期健康至关重要。我们的初步数据表明，分泌的信号因子印度刺猬（IHH）在TMJ开发中扮演着关键的作用。全局IHH消融导致盘和滑腔形成的失败，以及TGF-β1，PTHRP和润滑剂表达的丧失。 IHH产后消融导致润滑剂表达和碟片广告显着降低。这些发现导致了我们的中心假设：TMJ形成和产后功能都需要IHH信号传导。在AIM 1中，将进一步定义IHH信号在TMJ开发中的作用。最初，我们将关联IHH信号传导（GLI1激活）的时空模式o在TMJ发育过程中定义基因的刺猬受体，信号传感器和表型的表达。然后，我们将使用功能方法的损失和增益来在关键发育阶段删除TMJ单元中的平滑或修补1。在AIM 2中，我们将通过询问TGF-β1和PTHRP对其在TMJ中的靶细胞上进行IHH作用的假设，询问TGF-β1和/或PTHRP是否足以营救IHH-NULL TMJ表型，以及在IHH-Null Miese中类似的TMJ中的TMJ缺陷是否产生类似的TMJ缺陷。我们将进一步描述IHH-TGF-β和IHH-PTHRP信号传导途径及其在调节关节润滑剂生产和相关细胞类型的开发中的潜在相互作用。在AIM 3中，我们将研究关节润滑剂在IHH依赖性后TMJ维持中的作用。 HA和润滑剂在保护TMJ中的作用将通过分析的润滑剂（PRG4） - null和条件HA合酶2（HAS2） - 缺陷小鼠确定。我们还将测试通过全身或局部注射刺猬激动剂，PTHRP/PTH，TGF-β1或lubricin-和/has2-Expecters的局部递送，是否可以通过全身或局部注入刺猬激动剂，PTHRP/PTH，PTHRP/PTH，PTHRP/PTH，PTHRP/PTH，PTHRP/PTH，PTHRP/PTH，PTHRP/PTH和HAS2-表达矢量来挽救TMJ缺陷。总而言之，该项目将提供有关TMJ形成和维护中的刺猬信号传导的新颖，重要和深远的信息。我们的救援实验应提供原则上的证明，即包括碟片广告在内的TMJ缺陷可以接受治疗干预。