Role of BCL11B in development of the craniofacial skeleton

颅缝早骨化是临床上最重要的发育。 头盖骨穹隆紊乱，每2,250名活产儿中就有1名。这种疾病的后遗症包括受限 颅骨扩大，面中部发育不良，颅内压升高，以及颅面畸形，所有这些都是 它们会对呼吸、感觉系统和认知产生负面影响。 颅缝是一种纤维细胞结构，它将颅骨的硬板隔开并限制颅骨。 由拉力和压缩力引起的变形。保持缝合口的通畅是匹配的关键 随着婴儿大脑大小的爆炸性增加，头骨扩大--在第一次出生时，每周最高可达2.4毫米 生命的一年。人们对颅缝专利状态的保存机制知之甚少- 正是这些机制的失败导致了颅缝融合。颅缝合并症的遗传学基础 只有大约25%的患者已知，但这些突变导致早产的机制 骨缝的骨化还没有完全被理解。对缝合结构的分子和力学理解 通畅性将促进开发新的方法来诊断患者并创建针对患者的 治疗，这将提高颅缝融合症患者的生活质量。手术干预创造了一种 随着颅内体积的增加和颅内压的降低，头部形状变得更加正常 一个多世纪以来颅缝融合症治疗的主力军 这项建议的目的是确定维持高血压的机制(S)和基因网络。 转录调节蛋白BCL11B的缝合通畅性。我们的中心假设是BCL11B 维持缝合间充质中的骨祖细胞处于未成熟阶段，并通过调节 抑制成骨分化程序的基因网络的表达。我们将对此进行测试 通过实现两个具体目标来实现假设。在第一个目标中，我们将利用我们的体外模型来确定 成骨分化与BCL11B的表达水平有关。在第二个目标中我们将确定基因 网络调控BCL11B在颅缝间充质中的表达。 我们的新的小鼠模型将有助于识别BCL11B通过 控制缝合通畅性，并指导结合分子遗传分析的新策略的开发 并对颅缝早闭进行初步诊断分类。这一知识将改善 通过改进诊断、加强遗传咨询和创建 针对患者的具体治疗。我们有记录在案的指导各级学生的专业知识。剪裁- 这份提案中描述的边缘技术将为本科生提供出色的培训机会， 专业生和研究生。

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.