INTEGRATED RESEARCH OF FUNCTIONAL GENOMICS AND CRANIOFACIAL MORPHOGENESIS

描述（由申请人提供）：在本申请中，我们建议将我们在功能基因组学和颅面形态学/畸形学方面的研究整合到FaceBase联盟中。具体来说，我们将集中在下颌骨和上颌骨的发展。涉及这些面骨的先天性畸形显著影响生活质量 因为我们的脸就是我们的身份例如，下颌骨畸形，从颌骨发育不全到小颌畸形是一种常见的畸形，并出现在多种综合征中。小颌畸形不仅表现为面部畸形，还可引起腭裂和气道阻塞，如皮埃尔-罗宾序列。上颌骨有助于面中部的形成。上颌骨发育不全通常与腭裂有关，并且已经描述了六十多种不同的综合征。尽管它们的重要性，调节面骨发育的机制是相对不确定的。这是我们知识的一个重大差距，也是为研究界创造宝贵资源的一个重要机会。拟议的工作是一个合乎逻辑的进展，从我们目前的发言项目内的FaceBase联盟腭的发展。在过去的五年里，我们已经在FaceBase中心存放了近200个硬组织和软组织扫描和125个微阵列基因表达数据集。正如其他研究人员在主要国际会议和出版物上的发言所示，这些数据集已经证明了它们的实用性。同样重要的是，我们的团队在FaceBase Consortium、枢纽网站设计、数据组织和演示中发挥了重要作用。基于我们的经验并与RFA-DE-14-004保持一致，我们建议研究面骨发育和畸形。在特定目标1中，我们将对下颌骨发育进行全球和特定的基因表达谱分析，并将这些数据集与细胞谱系和定量3D动态成像分析相结合。与FaceBase联盟内的本体组合作，我们将定义发育中下颌骨的解剖标志和形态测量参数。在具体目标2，我们将扩大我们的基因表达谱分析在发展中的上颌骨。我们将把这些信息与上颌骨的3D成像相关联，并与FaceBase联盟内的本体组合作定义解剖标志和参数。我们的数据将有助于面骨形成的分子调控机制的研究。在具体目标3中，使用这里生成的数据，我们将研究TGF？ 以及Msx 1信号网络在调控下颌骨发育中的作用，并探讨TGF？ 下游靶基因可以预防和挽救突变动物模型中的下颌骨缺陷。这项研究将展示我们在中心的数据集如何促进假设驱动的研究和合作的产生。由于口面裂患者面部骨缺损的患病率和定量研究的缺乏，我们提出的研究将填补空白，并为研究界提供重要的资源。

DESCRIPTION (provided by applicant): In this application, we propose to integrate our research in functional genomics and craniofacial morphology/dysmorphology within the FaceBase Consortium. Specifically, we will focus on the development of the mandible and maxilla. Congenital malformations involving these facial bones significantly impact quality of life because our face is our identity. For example, mandibular dysmorphogenesis ranging from agenesis of the jaw to micrognathia is a common malformation and appears in multiple syndromes. Micrognathia not only presents as a facial deformity but can also cause cleft palate and airway obstruction, such as in Pierre-Robin sequence. The maxilla contributes to mid-facial formation. Maxillary hypoplasia is often associated with cleft palate and has been described in more than sixty different syndromes. Despite their importance, the mechanisms that regulate facial bone development are relatively uncharacterized. This is a significant gap in our knowledge and an important opportunity to generate invaluable resources for the research community. The proposed work is a logical progression from our current spoke project within the FaceBase Consortium on palatal development. Over the past five years, we have deposited nearly 200 hard and soft tissue scans and 125 microarray gene expression datasets in the FaceBase hub. These datasets have demonstrated their utility, as shown by other researchers' presentations at major international conferences and publications. Equally importantly, our team has played a significant role in the FaceBase Consortium, the hub website design, data organization and presentation. Building on our experience and in alignment with RFA-DE-14-004, we propose to investigate facial bone development and malformations. In Specific Aim 1, we will perform global and specific gene expression profiling analysis of mandible development, and will integrate these datasets with cell lineage and quantitative 3D dynamic imaging analyses. In collaboration with the ontology group within the FaceBase consortium, we will define anatomical landmarks and morphometric parameters of the developing mandible. In Specific Aim 2, we will expand our gene expression profile analyses in the developing maxilla. We will correlate this information with 3D imaging of the maxilla and define anatomical landmarks and parameters in collaboration with the ontology group within the FaceBase consortium. Our data will facilitate the investigation of the molecular regulatory mechanism of facial bone formation. In Specific Aim 3, using the data generated here, we will investigate the role of the TGF? and Msx1 signaling network in regulating mandible development and test how manipulation of TGF? downstream target genes can prevent and rescue mandible defects in mutant animal models. This study will showcase how our datasets at the hub can facilitate the generation of hypothesis-driven research and collaborations. Because of the prevalence of facial bone defects in orofacial clefting patients and the lack of quantitative studies in this are, our proposed study will fill a void and provide a significant resource for the research community.