Technology Project: Genetic Tools and Resources for Orofacial Clefting Research

描述（由申请人提供）：本修订申请的目的是识别和表征小鼠颅面（CF）疾病，这些疾病是人类颅面畸形的可靠遗传和生理模型，并与科学公众分享这些模型。由于人类的极端异质性以及环境和营养变量的多样性，在人群中发现CF疾病的遗传原因是困难的，所有这些因素都在导致CF疾病中起作用。因此，在受控环境中维持具有明确遗传背景的动物模型对于CF基因的发现是重要的。此修订应用程序的目标是通过FaceBase鼠标存储库为FaceBase研究人员和更广泛的CF研究社区提供CF畸形的新小鼠模型，从而支持CF研究。利用我们在杰克逊实验室的大型育种和研究群体中筛选表型偏差的完善计划，我们正在进行的ENU突变计划，以及通过参与nih范围内的敲除小鼠表型计划（KOMP2）获得新开发的菌株，我们将识别，表征表型和遗传特征，并分发CF疾病的新型小鼠模型。这些将包括CF表型的全部范围，包括颅骨形态学，牙列，视力和听力缺陷以及口面裂模型。对于大多数模型，我们将使用高通量测序技术确定致病基因。总之，该资源中的模型将为理解人类CF疾病的基础提供关键工具。！

DESCRIPTION (provided by applicant): The objectives of this revision application are to identify and characterize craniofacial (CF) disorders in mice that are reliable genetic and physiological models for human craniofacial dysmorphologies and to share these models with the scientific public. Discovery of the genetic cause of CF disease in human populations is difficult due to extreme heterogeneity in humans and to the diversity of environmental and nutritional variables, all of which have a role in resulting CF diseases. Consequently, animal models with defined genetic backgrounds maintained in controlled environments are important for CF gene discovery. The goal of this revision application is to support CF research by providing new mouse models of CF dysmorphologies to FaceBase investigators, and the broader CF research community, via the FaceBase Mouse Repository. Utilizing our well- established program to screen for phenotypic deviants in The Jackson Laboratory's large breeding and research colonies, our ongoing ENU mutagenesis program, and access to newly developed strains via our participation in the NIH-wide Knockout Mouse Phenotyping Program (KOMP2), we will identify, characterize phenotypically and genetically, and distribute novel mouse models of CF disorders. These will include the full range of CF phenotypes, including defects in skull morphology, dentition, vision, and hearing as well as models of orofacial clefting For most models, we will identify the causative gene using high throughput sequencing technologies. Together, the models within this resource will provide critical tools for understanding the basis of CF disorders in humans. ! PUBLIC HEALTH RELEVANCE: Craniofacial disorders are apparent in approximately 1 in 800 live births, representing nearly 75% of all human congenital malformations visible in newborns. This highly diverse group of disorders may include one or more malformations such as cleft lip and palate, abnormal morphology of the skull, face, or jaws, misshapen or missing teeth, and eye and ear abnormalities, with or without impaired sight or hearing. Causes for these disorders have been found to be both genetic and environmental, or the result of interaction between the two. Discovery of the genetic cause of disease in human populations is difficult due to extreme heterogeneity in humans and to the diversity of environmental and nutritional variables. Consequently, animal models with defined genetic backgrounds maintained in controlled environments are of particular importance for craniofacial gene discovery. The research in this project will provide new mouse models for specific craniofacial disorders and for basic research to understand biological systems that regulate the formation of the skull and face. Mouse models enable scientists to understand the causes and pathologies of similar human phenotypes so that prevention strategies or therapeutics can be developed. In addition, therapies or drugs can be tested on mouse models prior to human trials to assess efficacy and safety.