Regulatory Genes in Temporomandibular Joint Development

描述（由申请人提供）：我研究的总体目标是阐明颞下颌关节（TMJ）形成和维持的分子机制，TMJ是一种仅在哺乳动物中发现的高度特化的滑膜关节。目前，缺乏有关参与这些过程的分子信号的信息。以往的研究表明，在肢体中，控制滑膜关节形成的调控基因在脊椎动物中是高度保守的。该建议中包括的研究是基于这样的假设，即“调节滑膜关节发育的基本遗传机制是保守的，但TMJ特异性基因也参与了TMJ形成”。我将追求三个具体目标：在目标1中，我将详细描述小鼠TMJ发育的各个阶段，并研究一组已知控制肢体滑膜关节形成的明确调控基因的存在;在目标2中，我将使用高密度微阵列方法鉴定TMJ形态发生的特定调控因子和生物标记物;在目标3中，我将使用体内方法测试这些候选调控基因作为TMJ形态发生介质的相关性。总的来说，这些研究旨在缩小目前关于TMJ生物学的知识差距，这是设计颞下颌关节紊乱病新治疗方法的基本步骤，颞下颌关节紊乱病是一个影响约12%美国人口的重大健康问题。

Description (provided by applicant): The overall goal of my research is to elucidate the molecular mechanisms involved in the formation and maintenance of the temporomandibular joint (TMJ), a highly specialized synovial joint found only in mammals. Presently, there is a lack of information about the molecular signals participating in these processes. Previous studies in the limb have indicated that regulatory genes controlling the formation of synovial joints are highly conserved among vertebrates. Studies included in this proposal are based on the hypothesis that "the basic genetic mechanisms regulating synovial joint development are conserved, but TMJ specific genes are also involved during TMJ formation". I will pursue three specific aims: in Aim 1 I will detail the stages of TMJ development in the mouse and investigate the presence of a well-defined group of regulatory genes known to control synovial joint formation in the limb; in Aim 2, I will identify specific regulators and biological markers of TMJ morphogenesis using a high density microarray approach; and in Aim 3, I will test the relevance of these candidate regulatory genes as mediators of TMJ morphogenesis using in vivo approaches. Collectively, these studies aim to close the current knowledge gap on the biology of the TMJ, a fundamental step toward designing novel therapeutic approaches for temporomandibular joint disorders, a significant health problem affecting approximately 12% of the U.S. population.