Regeneration of the Developing Chick Elbow Joint

描述(由申请人提供)：滑膜关节，如组成肘关节、膝盖和髋关节的关节，对日常生活中的功能非常重要。先天性缺陷、疾病和滑膜关节的创伤，特别是组成关节的关节软骨，正在使数十亿人虚弱。由于缺乏完全的关节置换，严重缺乏使关节恢复正常功能状态的治疗方法。阻碍临床措施进展的是关节软骨固有的修复或再生能力。因此，在测试和使用基于再生的关节修复程序，即再生医学之前，必须了解构成关节的组织的再生过程。然而，到目前为止，还没有一项关于滑膜关节再生的研究。研究人员提出了节理再生模型和研究节理再生过程的新方法。使用胚胎雏鸡模型，她的初步数据显示，假定的肘关节能够在移除后再生，这种能力随后随着发育年龄的增加而丧失，证据是肘关节的缺乏和元素之间的软骨融合。提出的关节再生模型认为，组成肘关节、肱骨、桡骨和尺骨的预期骨骼元素的细胞首先被观察到为连续的间充质凝聚。观察到与软骨形成前期或早期凝结相关的基因。随后，这些基因在关节形成区域下调，调控关节形态发生的基因在再生关节中表达。研究人员的模型声称，在愈合过程中缺乏关节形态发生信号，导致四肢中骨骼元素的形成没有肘关节的介入。除了这种关节再生模型外，她还假设，由于成纤维细胞生长因子家族成员(S)的存在和/或激活，鸡肘能够在移除后启动再生。根据对尾目动物(火蜥蜴和蝾螈)、无尾两栖动物(蛙)和斑马鱼再生肢体/鳍的研究，有强有力的证据表明，在再生的早期阶段需要成纤维细胞生长因子信号。通过组织学、细胞标记、显微镜和基因表达，研究人员将验证关节再生模型。使用生长因子传递(功能获得)、抑制物分析(功能丧失)和RT-PCR，她将验证FGFs在启动再生中的作用。这个项目的长期目标是阐明再生组成关节的组织所需的因素，包括肌肉、骨骼和软骨。具体目的是为了检验关节再生模型和发育中的雏鸡关节再生需要成纤维细胞生长因子(S)的假说。这项工作将奠定基础，将在联合开发和再生医学领域产生重大影响。

DESCRIPTION (provided by applicant): Synovial joints such as those that comprise the elbow, knee, and hip are extremely important for functioning in everyday life. Congenital defects, disease, and trauma to synovial joints, in particular to the articular cartilage that comprises a joint, are debilitating to billions of people. Short of total joint replacement, therapies to bring the joint back to its normal functioning condition are sorely lacking. Impeding the progress of clinical measures is the inherent inability of articular cartilage to repair or regenerate itself. Thus, before joint repair procedures based on regeneration, i.e., regenerative medicine, are to be tested and utilized, there must be an understanding of the regeneration process of the tissues that comprise a joint. Until now, however, there has not been a study focused on regeneration of a synovial joint. The investigator proposes a model of joint regeneration and a novel means with which to study the regeneration process. Using the embryonic chick model, her preliminary data show that the presumptive elbow joint is able to regenerate following removal, and this ability is subsequently lost with increasing developmental age as evidenced by the lack of an elbow joint and what appear as cartilage fusions between elements. The proposed model of joint regeneration asserts that cells of the prospective skeletal elements that comprise the elbow, the humerus, radius, and ulna are first observed as continuous mesenchymal condensations. Genes associated with prechondrogenic or early condensations are observed. Subsequently, these genes are down regulated in the region of joint formation and genes regulating joint morphogenesis are expressed in the regenerating joint. The investigator' model purports that lack of joint morphogenetic signals during the healing process, results in limbs in which the skeletal elements are formed without an intervening elbow joint. In addition to this model of joint regeneration, she hypothesizes that the chick elbow is able to initiate regeneration following removal because of the presence and/or activation of a member(s) of the fibroblast growth factor (FGF) family. Based on studies of regenerating limbs/fins in urodeles (salamanders and newts), anurans (frogs), and zebrafish, there is strong evidence that Fgf signaling is required for the early stages of regeneration. Using histology, cell labeling, microscopy, and gene expression, the investigator will verify the model of joint regeneration. Using growth factor delivery (gain of function), inhibitor analysis (loss of function), and RT-PCR, she will verify a role for FGFs in the initiation of regeneration. The long-term goal of this project is to elucidate the factors required to regenerate the tissues that make up a joint, including muscle, bone, and cartilage. The specific aims are designed to test the model of joint regeneration and the hypothesis that Fgf(s) is required for the initiation of joint regeneration in the developing chick. This work will lay a foundation that will have significant implications in the fields of joint development and regenerative medicine.