Craniofacial Development and Disease

描述（由申请人提供）：为了最大限度地减少和预防颅面异常，必须了解个体畸形综合征的具体原因。然而，这需要对胚胎发育过程中形成头部和面部发育的正常发育事件进行深入了解。头部和面部的大部分组织，包括骨、软骨、结缔组织和外周神经系统组织，都来自于一种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育过程中神经嵴细胞发育缺陷而发生的。因此，研究神经嵴细胞如何以及何时形成，是什么引导神经嵴细胞到达其最终目的地，是什么使神经嵴细胞存活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是至关重要的。在这个提议中，我们研究了Treacher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柯林斯综合征是由于胚胎发育过程中发生的发育缺陷而引起的，其中神经嵴细胞生成不足，无法形成正常的头部和面部。我们已经确定了一个广泛的机制，通过它我们可以防止典型的Treacher柯林斯综合征的颅面异常的发展，并在本提案中，我们完善这一过程，以促进未来的临床应用。此外，由于我们的Treacher柯林斯综合征小鼠模型是少数几个表现出神经嵴细胞形成缺陷的小鼠动物模型之一，我们已经使用该模型来鉴定对神经嵴细胞和颅面发育重要的新基因。为了这个建议的目的，我们专注于一个基因，称为Nr6a1，这似乎是神经嵴细胞形成过程中的关键，因此是至关重要的正常颅面发育。 公共卫生相关性：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，并对国家卫生保健预算产生重大影响。Treacher柯林斯、Pierre Robin和Waardenburg综合征等疾病，沿着无裂脑畸形和颅缝早闭症等，具有严重的终身功能、美学和社会后果，对儿童和父母都是毁灭性的。综合手术、牙科护理、心理咨询和康复有助于改善问题，但多年来代价高昂。疾病控制中心估计，每年治疗唇腭裂儿童的终生费用为6.97亿美元。畸形综合征如Treacher柯林斯的产后治疗，通过全面的，良好的协调和综合策略，可以提供令人满意的管理每一个条件。然而，结果往往是可变的，很少完全纠正，因此需要投入相当大的努力，以开发预防的治疗途径。这只能来自于对个体畸形综合征的确切病因学和发病机制的深刻理解，这是建立在对调节神经嵴细胞图案形成和颅面发育的正常事件的透彻理解之上的。

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.