Role of BCL11B in development of the craniofacial skeleton

BCL11B 在颅面骨骼发育中的作用

• 批准号: 9351840
• 负责人: MARK E LEID
• 金额: $ 44.1万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-11 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9351840
• 关键词: Bilateral; Biological Markers; Biological Preservation; Calvaria; Caregivers; Cells; Child; Classification; Clinical; Cognition; Congenital abnormal Synostosis; Couples; Craniosynostosis; Development; Diagnosis; Diagnostic; Disease; Dysmorphology; Exhibits; Failure; Future; Gene Expression; Genes; Genetic; Genetic Counseling; Genetic Enhancement; Goals; Head; Infant; Intracranial Hypertension; Intracranial Pressure; Joint structure of suture of skull; Knowledge; Legal patent; Life; Link; Live Birth; Maintenance; Mesenchymal; Mesenchyme; Molecular; Molecular Genetics; Mus; Mutation; Neural Crest; Operative Surgical Procedures; Patients; Phenotype; Physiologic Ossification; Positioning Attribute; Quality of life; Regulator Genes; Research Personnel; Respiration; Role; Shapes; Skeleton; Skull Disorder; Structure; Surgical sutures; Techniques; Testing; Transcript; Transcription Regulatory Protein; Wild Type Mouse; base; bone; brain size; career; coronal suture; coronal synostosis; craniofacial; craniofacial development; cranium; developmental disease; disease classification; follow-up; genetic analysis; graduate student; human disease; improved; in vitro Model; loss of function; midfacial hypoplasia; mouse model; novel; osteogenic; osteogenic protein; osteoprogenitor cell; premature; programs; sensory system; student mentoring; training opportunity; transcriptome; undergraduate student

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.

颅骨突变，颅骨的过早骨化，是最临床的重要发育 颅骨伏特的障碍，在2,250个活率中发生约1个。 颅骨扩张，中间性发育不全，颅内增加增加和颅面畸形学，所有这些 其中的负面影响反应，感觉系统和认知。 颅骨缝合线是纤维球结构，可将头骨骨骼的刚性板分开并限制头骨 由于拉伸力和压缩力引起的变形。 颅骨扩张，婴儿大脑大小的爆炸性增加 - 第一次，最高2.4毫米PERES周 生命的一年。 这是导致颅突的the机制的失败。 在on -ly中已知约25％的机制 缝隙骨化尚不完全理解。 通畅将有助于开发新的途径，以诊断患者并创建特定于患者的患者 治疗方法将改善颅骨静态病的寿命。 更正常的头部形状随颅内体积增加和颅内压力降低。 颅突的主要治疗中的支柱 该提案的目的是确定维护的基础机制和基因网络 转录调节蛋白BCl11b的缝合通畅是我们的中心假设 在不成熟的阶段阶段阶段soby一段时间以来，在不成熟的阶段阶段阶段阶段中保持骨化剂 抑制成骨区分程序的基因网络的表达。 通过在第一个目标中实现两个特定目标，我们将利用我们的体外模型来确定 在第二个目标中，成骨与Bcl11b的表达水平相关联。 网络常规BCl11b在钙缝线的缝合间质中。 我们的新型鼠标模型将促进BCL11B通过的基因调节网络的识别 控制缝合通畅，并指导分子遗传分析的新策略的发展 随着颅突的主要诊断分类。 疾病剧院的患者改善了诊断，遗传咨询的增强和创造 特定于患者的治疗方法。 在此描述的边缘技术为本科生提供了出色的培训机会， 专业和研究生。