RESEARCH ON FUNCTIONAL GENOMICS, IMAGE ANALYSIS AND RESCUE OF CLEFT PALATE

描述(由申请人提供)：脸部基础联盟的发展需要一个全面的研究合作，以促进关于面部中部发育和畸形的新数据和现有数据的收集、组织和优化利用。我们实验室在研究腭裂的分子和细胞机制方面有很长的历史。我们已经制定了一项建议，以我们的实力为基础，并将重点放在选定的和高度临床相关的腭裂动物模型的基因组和成像分析上。具体地说，我们将使用代表人类完全性和粘膜下腭裂缺陷的TGFb、Tgfbr、Smad4、Msx1和FGFR2突变动物模型作为我们的切入点。利用这些动物模型，我们将与几位科学家密切合作，解决数控细胞命运决定的调控机制。具体地说，我们将与加州理工学院的Marianne Bronner-Fraser博士合作，研究传统脊椎动物模型的神经脊基因调控网络是否保守，并可能在腭裂发生过程中发挥其调节功能。与南加州大学的Joseph Hacia博士合作，我们将发现转化生长因子-b信号网络的关键组件，这些组件专门参与调控腭裂形成过程中计算机控制细胞的命运。与加州理工学院的Scott Fraser博士合作，我们将使用microMRI和microCT生成全面和动态的腭裂和畸形的三维图像。最后，我们开发了一种策略来筛选基因调控网络中的特定干预点，这将使我们能够开发预防和拯救腭裂的治疗策略。我们的共同努力不仅将为面部基础联盟创造巨大的资源，还将为未来颅面部出生缺陷的翻译研究提供广泛合作的机会。 公共卫生相关性：腭裂是人类最常见的先天性出生缺陷之一。通过合作的方法，本研究计划旨在研究腭裂的信号机制，并为未来的腭裂研究提供关键的基因组和成像资源。更重要的是，这一建议将揭示干预的关键点，可以为未来腭裂的预防和抢救提供针对性的指导。

DESCRIPTION (provided by applicant): The development of the Face Base Consortium calls for a comprehensive research collaboration to facilitate data collection, organization, and optimized utilization of new and existing data on mid-facial development and malformations. Our laboratory has a long history of investigating the molecular and cellular mechanism of cleft palate. We have developed a proposal that builds on our strength and will focus on genomic and imaging analysis of selected and highly clinically relevant cleft palate animal models. Specifically, we will use the Tgfb, Tgfbr, Smad4, Msx1 and Fgfr2 mutant animal models that represent complete and sub-mucous cleft palate defects in humans as our entry point. Taking advantage of these animal models, we will work closely with several scientists to address the regulatory mechanism of CNC cell fate determination. Specifically, working with Dr. Marianne Bronner-Fraser at California Institute of Technology (Caltech), we will investigate whether the neural crest gene regulatory network of traditional vertebrate models is conserved and may exert its regulatory function during palatogenesis. In collaboration with Dr. Joseph Hacia at USC, we will discover critical components of the Tgf-b signaling network that are specifically involved in regulating the fate of CNC cells during palatogenesis. Working with Dr. Scott Fraser at Caltech, we will generate comprehensive and dynamic three-dimensional images of palatogenesis and malformations using microMRI and microCT. Finally, we have developed a strategy to screen for specific points of intervention within the gene regulatory network that will allow us to develop therapeutic strategies to prevent and rescue cleft palate. Our collective effort will not only generate tremendous resources for the Face Base Consortium but will also offer opportunities for extensive collaborations for future translational research on craniofacial birth defects. PUBLIC HEALTH RELEVANCE: Cleft palate represents one of the most common congenital birth defects in the human population. Through a collaborative approach, this research program is designed to investigate the signaling mechanism of cleft palate and to provide crucial genomic and imaging resources for future cleft palate research. More importantly, this proposal will reveal crucial points of intervention, which can be targeted for future prevention and rescue of cleft palate.