Craniofacial Development and Disease

描述(申请人提供)：为了最大限度地减少和预防颅面畸形，了解个别畸形综合征的具体原因是至关重要的。然而，这需要深入了解在胚胎发育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、软骨、结缔组织和周围神经系统组织，都来自一种称为神经脊的细胞群。大多数颅面综合征被认为是由于胚胎发育过程中神经脊细胞发育的缺陷所致。因此，有必要研究神经脊细胞是如何以及何时形成的，是什么引导神经脊细胞到达它们的最终目的地，是什么让神经脊细胞存活，以及神经脊细胞是如何决定成为结缔组织和神经组织的软骨或骨的。在这项建议中，我们研究了Treacher Collins综合征的小鼠模型，该模型复制了人类严重的颅面部疾病。Treacher Collins综合征是由于胚胎发育过程中发生的发育缺陷引起的，在胚胎发育过程中，神经脊细胞的生成不足，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Treacher Collins综合征典型的颅面畸形的发展，在这项建议中，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综合征小鼠模型代表了少数显示神经脊细胞形成缺陷的小鼠动物模型之一，我们使用该模型来识别对神经脊细胞和颅面发育重要的新基因。在这项研究中，我们将重点放在一个名为Nr6a1的基因上，它似乎对神经脊细胞的形成过程至关重要，因此对正常的颅面发育至关重要。 公共卫生相关性：头面部异常约占新生儿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。诸如Treacher Collins、Pierre Robin和Waardenburg综合征，以及全脑畸形和颅缝早闭等疾病，具有严重的终生功能、审美和社会后果，对儿童和父母都是毁灭性的。全面的手术、牙科护理、心理咨询和康复帮助缓解了这些问题，但在多年的时间里付出了巨大的代价。疾病控制中心估计，仅治疗每年出生的唇裂和/或腭裂儿童的终身成本就高达6.97亿美元。通过全面、协调和综合的策略对Treacher Collins等畸形综合征进行产后治疗，可以对每种情况提供令人满意的管理。然而，结果往往是可变的，很少是完全纠正的，因此需要投入大量的精力来开发预防的治疗途径。这只能来自对个体畸形综合征的确切病因和发病机制的深入认识，这是建立在对调节神经脊细胞模式和颅面发育的正常事件的透彻理解的基础上的。

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.