The Molecular Genetics and Cell Biology of Jaw Joint Morphogenesis

描述（由申请人提供）：关节是复杂的解剖结构，有助于骨骼元素的衔接。斑马鱼幼鱼的下颌关节为理解关节形成的分子遗传学和细胞生物学提供了一个简化的模型系统，其中信号分子指导干细胞形成构成斑马鱼幼鱼骨骼的软骨和关节。我将检查一种基因，我假设这种基因可以阻止关节区域的软骨形成。此外，我建议研究控制细胞运动、粘附和排斥的分子“规则”，以确保细胞位于其适当的解剖位置。此外，我将发现斑马鱼颌关节形成所需的新基因。这些研究将有助于我们对人类关节发育和疾病的理解。斑马鱼幼虫是这些研究的最佳系统，因为它们是透明的，并且是外部发育的。因此，我建议研究的所有细胞过程都可以在发育中的动物身上看到。我将监测我感兴趣的基因在何时何地被激活，并使用先前验证过的工具来减少和增加它们的功能。正常功能的扰动将促进在颌骨关节形成过程中基因各自作用的发现。与公共卫生相关：这些研究调查了与癌症有关的信号分子的正常功能。了解致癌基因如何正常发挥作用对于理解它们在人类疾病中的作用至关重要。此外，我的研究将有助于理解信号分子如何控制从单个干细胞样前体细胞到多种细胞类型的发展。这一知识对干细胞治疗具有巨大的价值。

DESCRIPTION (provided by applicant): Joints are complex anatomical structures that facilitate the articulation of skeletal elements. Jaw joints of larval zebrafish provide a simplified model system for understanding the molecular genetics and cell biology of joint formation, where signaling molecules instruct stem-like cells to form the cartilages and joints that constitute the young zebrafish skeleton. I will examine a gene that I hypothesize prevents cartilage formation in the joint region. In addition, I propose to examine the molecular "rules" that govern cell movement, adhesion, and repulsion to ensure cells reside at their proper anatomical site. Furthermore, I will discover new genes that are required for zebrafish jaw joint formation. These studies will aid in our understanding of human joint development and disorders. Zebrafish larvae are the optimal system for these studies as they are optically transparent, and develop externally. Therefore, all of the cellular processes I propose to study can be witnessed in the developing animal. I will monitor where and when the genes I am interested in are turned on, and will reduce and increase their function using previously validated tools. Perturbation of normal function will foster discovery of the respective roles for genes during jaw joint formation. Relevance to public health: These studies investigate the normal function of signaling molecules that are implicated in cancer. A working knowledge of how cancer-causing genes function normally is paramount to understanding their role in human disease. Furthermore, my studies will aid in understanding how signaling molecules control the development of a wide array of cell types from a single stem-like precursor cell. This knowledge is of tremendous value for stem cell therapeutics.