Craniofacial Development and Disease

颅面发育与疾病

• 批准号: 8291876
• 负责人: Paul Trainor
• 金额: $ 39.35万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291876
• 关键词: Accounting; Animal Model; Apoptosis; Apoptotic; Budgets; Cartilage; Cell Death; Cell Maintenance; Cells; Centers for Disease Control and Prevention (U.S.); Child; Cleft Lip; Cleft Palate; Congenital Abnormality; Connective Tissue; Counseling; Craniofacial Abnormalities; Craniosynostosis; Data; Defect; Dental Care; Destinations; Development; Disease; Embryo; Embryonic Development; Employee Strikes; Esthetics; Etiology; Event; Exhibits; Face; Future; Gene Proteins; Genes; Genetic; Genotype; Head; Healthcare; Human; Individual; Infant Mortality; Knockout Mice; Maintenance; Mandibulofacial Dysostosis; Maps; Modeling; Mus; Names; Nerve Tissue; Neural Crest; Neural Crest Cell; Nuclear Orphan Receptor; Operative Surgical Procedures; Parents; Pathogenesis; Pattern; Peripheral Nervous System; Play; Population; Prevention; Process; Rehabilitation therapy; Robin bird; Role; Severities; Shapes; Stem cells; Syndrome; Therapeutic; Tissues; Waardenburg syndrome; X Chromosome; bone; chromatin immunoprecipitation; clinical application; cost; craniofacial; disorder prevention; epithelial to mesenchymal transition; life time cost; loss of function; malformation; migration; mouse model; mutant; nerve stem cell; neural plate; novel; novel therapeutics; pluripotency; prevent; psychologic; public health relevance; social; stable cell line; stem

DESCRIPTION (provided by applicant): In order to minimize and prevent craniofacial anomalies, it is essential to understand the specific cause of individual malformation syndromes. However, this requires a deep appreciation of the normal developmental events that shape head and facial development during embryogenesis. The majority of the tissues of the head and face including bone, cartilage, connective and peripheral nervous system tissue are derived from a cell population called the neural crest. Most craniofacial syndromes are thought to occur due to a defect in the neural crest cell development during embryogenesis. Thus it is essential to study how and when neural crest cells are formed, what guides neural crest cells to their final destinations, what keeps neural crest cells alive and also how neural crest cells decide to become cartilage or bone of connective and nerve tissue. In this proposal we study a mouse model of Treacher Collins syndrome, which replicates the severe craniofacial disorder in humans. Treacher Collins syndrome arises due to a developmental defect occurring during embryogenesis in which insufficient neural crest cells are generated to make a normal head and face. We have identified a broad mechanism by which we can prevent the development of craniofacial anomalies typical of Treacher Collins syndrome and in this proposal we refine this process to facilitate future clinical applications. In addition, since our mouse model of Treacher Collins syndrome represents one of few mouse animal models that exhibit a defect in neural crest cell formation, we have used this model to identify new genes that are important for neural crest cell and craniofacial development. For the purpose of this proposal we focus on one gene, called Nr6a1, which appears to be critical for the neural crest cell formation process and as such is essential for normal craniofacial development. PUBLIC HEALTH RELEVANCE: Craniofacial abnormalities account for approximately one third of all birth defects in new born kids, are a major cause of infant mortality and dramatically impact upon national health care budgets. Disorders such as Treacher Collins, Pierre Robin and Waardenburg syndromes, along with holoposencephaly and craniosynostosis to name a few, have serious lifetime functional, esthetic and social consequences that are devastating to children and parents alike. Comprehensive surgery, dental care, psychological counseling and rehabilitation help ameliorate the problems, but at a great cost over many years. The Center for Disease Control estimates that the lifetime cost of treating the children born each year with cleft lip and/or cleft palate alone to be $697 million. Post-natal treatment of malformation syndromes such as Treacher Collins through comprehensive, well-coordinated and integrated strategies can provide satisfactory management of each condition. However, the results are often variable and rarely fully corrective, hence considerable effort needs to be invested into developing therapeutic avenues of prevention. This can only come from a deep appreciation of the precise etiology and pathogenesis of individual malformation syndromes, which is built upon a thorough understanding of the normal events that regulate neural crest cell patterning and craniofacial development.

描述（由申请人提供）：为了最大程度地减少和预防颅面异常，必须了解单个畸形综合征的特定原因。但是，这需要对塑造胚胎发生过程中头部和面部发育的正常发育事件深表认识。头部和面部的大多数组织，包括骨骼，软骨，结缔组织和周围神经系统组织，源自称为神经rest的细胞种群。人们认为，大多数颅面综合征被认为是由于胚胎发生过程中神经rest细胞发育的缺陷而发生的。因此，研究神经rest细胞的方式以及何时形成，是什么指导神经rest细胞到其最终目的地，使神经rest活着的原因以及神经rest细胞如何决定成为软骨或神经组织的骨骼。在此提案中，我们研究了一种背叛者柯林斯综合征的小鼠模型，该模型复制了人类严重的颅面疾病。 Treacher Collins综合征是由于在胚胎发生过程中出现的发育缺陷而产生的，在胚胎发生过程中，神经Crest细胞的产生不足以使头部和面部正常。我们已经确定了一种广泛的机制，通过该机制，我们可以防止Treacher Collins综合征典型的颅面异常发展，在此提案中，我们完善了这一过程，以促进未来的临床应用。此外，由于我们的treacher柯林斯综合征的小鼠模型代表了少数显示神经rest细胞形成缺陷的小鼠动物模型之一，因此我们使用该模型来识别对神经纹山细胞和颅面发育很重要的新基因。出于该提议的目的，我们关注一个称为NR6A1的基因，这对于神经rest细胞的形成过程至关重要，因此对于正常的颅面发育至关重要。 公共卫生相关性：颅面异常占新生儿童所有出生缺陷的三分之一，是婴儿死亡率的主要原因，并对国家卫生保健预算产生了巨大影响。诸如“野蛮者柯林斯”，皮埃尔·罗宾和瓦登堡综合症等疾病，以及holoposencephaly和Craniosynostosis，仅举几例，具有严重的终身功能性，审美和社会后果，这对儿童和父母都造成了破坏。全面的手术，牙科护理，心理咨询和康复有助于改善问题，但多年来的成本很大。疾病控制中心估计，每年用唇裂和/或left裂的儿童仅为6.97亿美元的终身成本。通过全面，协调良好的综合策略对畸形综合症（例如背叛者柯林斯）等畸形综合症的治疗可以提供令人满意的每种疾病的管理。但是，结果通常是可变的，而且很少完全纠正，因此需要大量努力用于开发预防治疗途径。这只能来自对个体畸形综合征的精确病因和发病机理的深刻欣赏，这是基于对调节神经crest细胞构成和颅面发育的正常事件的彻底理解。