Role of BCL11B in development of the craniofacial skeleton

颅缝早闭，即颅缝过早骨化，是临床上最重要的发育障碍。 颅骨穹窿疾病，约每2，250例活产中有1例发生。这种疾病的后遗症包括限制 颅骨扩张、面中部发育不全、颅内压升高和颅面畸形，所有 对呼吸、感觉系统和认知产生负面影响。 颅缝是纤维细胞结构，其将颅骨的刚性板分开并限制颅骨 由于张力和压力引起的变形。保持缝合通畅对于匹配至关重要 随着婴儿大脑体积的爆炸性增长，颅骨扩张-在第一个月期间，每周可达2.4毫米 年的生活。我们对颅缝的保护机制知之甚少- 正是这些机制的失效导致了颅缝早闭。颅缝早闭的遗传基础 只有大约25%的患者知道，但这些突变导致过早死亡的机制是未知的。 缝骨化不完全了解。缝合线的分子和机制的理解 通畅性将促进诊断患者的新途径的开发， 治疗，这将提高颅缝早闭患者的生活质量。手术干预， 更正常的头部形状，颅内容量增加，颅内压降低， 世纪以来颅缝早闭治疗主流 本提案的目的是确定维持以下功能的机制和基因网络： 通过转录调节蛋白BCL 11B的缝合通畅性。我们的中心假设是BCL11B 在未成熟阶段维持缝间充质中的骨祖细胞，并通过调节 抑制成骨分化程序的基因网络的表达。我们将测试这个 实现两个具体目标。在第一个目标中，我们将利用我们的体外模型来确定如何 成骨分化与BCL 11 B表达水平相关。在第二个目标中，我们将确定基因 BCL 11 B在颅缝间充质中的网络调节。 我们的新型小鼠模型将有助于识别BCL11B通过其表达的基因调控网络。 控制缝合的通畅性，并指导新策略的开发， 初步诊断为颅缝早闭。这些知识将提高生活质量， 通过改进诊断、加强遗传咨询和建立 针对患者的治疗。我们在指导各个级别的学生方面都有记录在案的专业知识。切割- 本提案中描述的边缘技术将为本科生提供出色的培训机会， 专业人员和研究生。

Craniosynostosis, the premature ossification of cranial sutures, is the most clinically important developmental disorder of the skull vault, occurring in ~ 1 in 2,250 live births. Sequelae of this disorder include restricted skull expansion, midfacial hypoplasia, increased intracranial pressure, and craniofacial dysmorphologies, all of which negatively impact respiration, sensory systems, and cognition. Cranial sutures are fibrocellular structures that separate the rigid plates of the skull bones and limit skull deformation due to both tensile and compressive forces. Maintenance of sutural patency is essential to match skull expansion with the explosive increase in brain size of infants—up to 2.4 mm per week during the first year of life. Little is known of the mechanisms underlying preservation of the patent state of cranial sutures— and it is the failure of these mechanisms that results in craniosynostosis. A genetic basis for craniosynostoses is known in only about 25% of patients but the mechanisms by which these mutations result in premature sutural ossification are incompletely understood. A molecular and mechanistic understanding of sutural patency will facilitate development of new avenues to diagnose patients and create patient-specific treatments, which will improve quality of life for craniosynostosis patients. Surgical intervention to create a more normal head shape with increased intracranial volume and reduced intracranial pressure has been the mainstay of craniosynostosis treatment for over a century The objective of this proposal is to identify mechanism(s) and gene networks underlying the maintenance of sutural patency by the transcriptional regulatory protein BCL11B. Our central hypothesis is that BCL11B maintains osteoprogenitors in the sutural mesenchyme at an immature stage and does so by regulating expression of a network of genes that suppresses the osteogenic differentiation program. We will test this hypothesis by achieving two specific aims. In the first Aim we will exploit our in vitro model to determine how osteogenic differentiation is tied to BCL11B expression levels. In the second Aim we will determine the gene network regulated BCL11B in the sutural mesenchyme of calvarial sutures. Our novel mouse models will facilitate identification of gene regulatory networks through which BCL11B controls sutural patency, and guide development of new strategies that couple molecular genetic analyses with primary diagnostic classification of craniosynostosis. This knowledge will improve quality of life for patients with the disease through improved diagnostics, enhanced genetic counselling, and creation of patient-specific treatments. We have documented expertise in mentoring students at all levels. The cutting- edge techniques described in this proposal will provide outstanding training opportunities for undergraduate, professional, and graduate students.