Craniofacial Development and Disease

颅面发育与疾病

• 批准号: 7792529
• 负责人: Paul Trainor
• 金额: $ 39.75万
• 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/7792529
• 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; 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; TP53 gene; 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）：为了尽量减少和预防颅面异常，有必要了解个体畸形综合征的具体原因。然而，这需要深入了解胚胎发生过程中塑造头部和面部发育的正常发育事件。头部和面部的大部分组织，包括骨骼、软骨、结缔组织和周围神经系统组织，都源自称为神经嵴的细胞群。大多数颅面综合征被认为是由于胚胎发生过程中神经嵴细胞发育缺陷而发生的。因此，有必要研究神经嵴细胞如何以及何时形成，什么引导神经嵴细胞到达最终目的地，什么使神经嵴细胞保持活力，以及神经嵴细胞如何决定成为结缔组织和神经组织的软骨或骨骼。在这项提案中，我们研究了特雷彻柯林斯综合征的小鼠模型，该模型复制了人类的严重颅面疾病。特雷彻柯林斯综合征是由于胚胎发生过程中发生的发育缺陷而产生的，其中产生的神经嵴细胞不足以形成正常的头部和面部。我们已经确定了一种广泛的机制，可以通过它来预防特雷彻柯林斯综合征典型的颅面异常的发展，并且在本提案中，我们改进了这一过程以促进未来的临床应用。此外，由于我们的 Treacher Collins 综合征小鼠模型是少数表现出神经嵴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嵴细胞和颅面发育重要的新基因。出于本提案的目的，我们重点关注一个名为 Nr6a1 的基因，该基因似乎对神经嵴细胞形成过程至关重要，因此对于正常颅面发育至关重要。 公共健康相关性：颅面畸形约占新生儿所有出生缺陷的三分之一，是婴儿死亡的主要原因，并对国家医疗保健预算产生巨大影响。特雷彻·柯林斯 (Treacher Collins)、皮埃尔·罗宾 (Pierre Robin) 和瓦登堡 (Waardenburg) 综合征等疾病，以及无脑畸形和颅缝早闭等疾病，会造成严重的终生功能、审美和社会后果，对儿童和父母来说都是毁灭性的。综合手术、牙科护理、心理咨询和康复有助于改善这些问题，但多年来花费巨大。疾病控制中心估计，仅治疗每年出生的唇裂和/或腭裂儿童的终生费用就高达 6.97 亿美元。通过全面、协调一致的综合策略，对特雷彻·柯林斯等畸形综合征进行产后治疗，可以对每种病症提供满意的治疗。然而，结果往往是可变的，并且很少能完全纠正，因此需要投入大量精力来开发预防的治疗途径。这只能来自于对个体畸形综合征的精确病因和发病机制的深入了解，而这种了解是建立在对调节神经嵴细胞模式和颅面发育的正常事件的透彻理解的基础上的。