Building the skull - normal and abnormal development

构建头骨 - 正常和异常发育

• 批准号: 2434887
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2434887
• 关键词: Building; skull; normal; abnormal; development

This project will focus on craniosynostosis, the premature fusion of one or more sutures separating the bones of the skull vault. A complex network of developmental mechanisms is involved in patterning and maintaining this complex system of bones, and a variety of genetic mutations can affect these processes to cause serious skull malformations. Oxford is a leading national referral centre in the surgical treatment of these malformations, enabling us study the entire process by which these arise from patient to mutation, and from mouse model to molecular pathogenesis.The project will exploit the large number of clinical samples available to explore specific hypotheses of causation. An early focus will involve investigation of the gene RUNX2, which encodes a master transcriptional regulator of ossification. There is likely to be the opportunity to interrogate whole genome sequence as part of the research programme of the new NHS Genomic Medicine Service diagnostics service. Potential epigenetic mechanisms of pathogenesis will be explored as well. To investigate pathophysiology, carefully selected mutations will be modelled in mice. We still know very little about what happens biologically in the cranial sutures themselves: these structures must achieve a delicate balancing act of enabling growth of new bone at the margins of the suture, whilst also ensuring that the mid-part of the suture remains open along its entire length. We explore how the suture works by mapping out the cellular hierarchy of activities from undifferentiated stem cell to fully formed osteoblast, comparing results between normal sutures and those from mice with targeted mutations. A specific focus will be to elucidate the pathogenic mechanisms by which craniosynostosis arises in a Zic1-mutated mouse, available in the laboratory. The opportunity to generate additional targeted mouse mutants using CRISPR/Cas9 genome editing may arise out of the human genetics investigations.Specific skills acquired will include: (i) use of web resources to interpret genomic information from human, mouse and other species; (ii) experimental techniques including cell culture, fluorescence-activated cell sorting (FACS), microscopy, single cell transcriptomics and next generation sequencing, in addition to basic molecular biology methodologies; (iii) training in husbandry and phenotypic analysis of mice, with acquisition of a personal license and (iv) bioinformatics approaches to analysis of large datasets including genome sequencing, single cell transcriptomics, or epigenomics (full support will be available through the Centre for Computational Biology). Additional generic and transferable skills training will be provided through the MRC-WIMM DPhil Course and the Medical Sciences Division's Skills Training Programme.

这个项目将集中在颅缝早闭，过早融合的一个或多个缝分开的骨头头骨穹窿。一个复杂的发育机制网络参与了这个复杂的骨骼系统的形成和维持，各种基因突变可能会影响这些过程，导致严重的颅骨畸形。牛津大学在外科治疗这些畸形方面是一个领先的国家转诊中心，使我们能够研究这些畸形从患者到突变，从小鼠模型到分子发病机制的整个过程。该项目将利用大量的临床样本来探索特定的因果关系假设。早期的重点将涉及研究基因RUNX 2，它编码骨化的主要转录调节因子。作为新的NHS基因组医学服务诊断服务研究方案的一部分，可能有机会询问全基因组序列。发病机制的潜在表观遗传机制也将探讨。为了研究病理生理学，将在小鼠中对精心选择的突变进行建模。我们对颅缝本身的生物学作用仍然知之甚少：这些结构必须实现微妙的平衡，使新骨在缝的边缘生长，同时也确保缝的中间部分沿其整个长度保持沿着开放。我们通过绘制从未分化的干细胞到完全形成的成骨细胞的细胞活动层次来探索缝合线的工作原理，比较正常缝合线和具有靶向突变的小鼠的缝合线之间的结果。一个具体的重点将是阐明发病机制，其中颅缝早闭症出现在Zic 1突变的小鼠，在实验室中。利用CRISPR/Cas9基因组编辑产生额外的靶向小鼠突变体的机会可能来自人类遗传学研究。获得的具体技能将包括：（i）使用网络资源解释来自人类，小鼠和其他物种的基因组信息;（ii）实验技术，包括细胞培养、荧光激活细胞分选（FACS）、显微镜、单细胞转录组学和下一代测序，除了基本的分子生物学方法外，还包括：（iii）在获得个人许可证的情况下进行饲养和小鼠表型分析方面的培训;（iv）采用生物信息学方法分析大型数据集，包括基因组测序、单细胞转录组学或表观基因组学（将通过计算生物学中心提供全面支持）。将通过MRC-WIMM哲学博士课程和医学科学司的技能培训方案提供额外的通用和可转移技能培训。