Prolonger progenitor maintenance sculpts the upper face

延长祖细胞保养塑造上脸

• 批准号: 9811478
• 负责人: Lindsey Anne Barske
• 金额: $ 24.9万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9811478
• 关键词: Address; Advisory Committees; Affect; Biology; Cartilage; Cells; Cleft Palate; Communities; Complex; Congenital Abnormality; Country; Craniosynostosis; Data; Defect; Dermal; Development; Developmental Biology; Dorsal; Educational workshop; Embryo; Exhibits; FGF20 gene; Face; Faculty; Foundations; Gene Expression; Genes; Genetic; Goals; Grant; Health; Human; Image; Impairment; Institution; Jaw; Knockout Mice; Maintenance; Mammals; Mediator of activation protein; Mentors; Mentorship; Mission; Modeling; Molecular; Morphology; Mus; National Institute of Dental and Craniofacial Research; Natural regeneration; Neural Crest; Nuclear Receptors; Osteogenesis; Pathway interactions; Pattern; Phase; Phenotype; Population; Positioning Attribute; Proteins; Public Health; Research; Research Personnel; Resources; Role; Schedule; Shapes; Signal Transduction; Skeleton; Stem cells; Testing; Training; Work; Writing; Yang; Zebrafish; apoAI regulatory protein-1; base; bone; career; career development; cartilage development; craniofacial; cranium; design; experience; experimental study; follow-up; gene function; genome-wide; imaging modality; in vitro Model; in vivo imaging; meetings; middle ear; mouse model; mutant; nerve stem cell; notch protein; novel; preservation; prevent; professor; progenitor; programs; skeletal; tenure track; tool; transcriptome sequencing; zebrafish development

Project Summary Prolonged Progenitor Maintenance Sculpts the Upper Face Though dozens of genes are known to participate in shaping the facial skeleton, how facial skeletal precursors are differentially allocated into cartilage versus bone fates in different parts of the face remains poorly understood. Dr. Mork's postdoctoral work in Dr. Gage Crump's lab at USC offers a new perspective on how the vertebrate skull is built, where prolonged maintenance of skeletal progenitors appears to underlie the increased proportion of directly-ossifying dermal bone relative to cartilage in the upper versus the lower face. Importantly for public health, many common craniofacial birth defects affecting various parts of the skull, including craniosynostosis, cleft palate, and middle ear bone abnormalities, could potentially be explained by precocious differentiation of skeletal progenitors. The aims outlined in this proposal take genetic and developmental approaches in zebrafish and mouse models, combined with sophisticated live-imaging and genome-wide expression analyses, to substantiate this new model of facial patterning. The proposed experiments will build from her extensive preliminary data to test the hypothesis that two novel targets of the key differentiation- suppressing Jagged-Notch pathway – Fibroblast Growth Factor 20 (Aim 1) and Nuclear Receptor 2f genes (Aims 2 & 3) – actively maintain cells in a progenitor state in the upper face of the developing embryo, thereby preserving dermal bone precursors at the expense of cartilage differentiation in the upper facial skeleton. Aims 1 & 3 will be initiated under the mentorship of Drs. Crump and Chai and completed during the R00 period, whereas Aim 2 is farther along and will be completed before the end of the K99 phase. This project has been designed to facilitate Dr. Mork's career goal of obtaining a position as a tenure-track Assistant Professor at a top-tier academic research institution. She plans to develop an independent research program relying on state-of-the-art genetic and imaging methods in both zebrafish and mouse models to address unresolved questions in craniofacial developmental biology with clear relevance for human health. During the K99 phase, she will benefit from continued mentorship in zebrafish development by Dr. Crump, crucial training in mouse craniofacial biology from her co-mentor Dr. Yang Chai, and additional career and scientific guidance at regularly scheduled meetings with her full Advisory Committee. Additional career development activities at USC, such as grant-writing and mentorship workshops, will prepare Dr. Mork for the transition to an independent faculty position during the R00 phase. As USC hosts one of the most experienced and thriving communities of craniofacial and skeletal biologists in the country, there are few better places that she could acquire the training, resources, and network of collaborators needed to establish herself as an independent investigator in craniofacial biology.

项目概要 长期的祖细胞维护塑造上脸 尽管已知有数十种基因参与塑造面部骨骼，但面部骨骼前体是如何形成的？ 面部不同部位的软骨与骨命运的分配差异仍然很差 明白了。 Mork 博士在南加州大学 Gage Crump 博士实验室的博士后工作为如何 脊椎动物头骨的形成，其中骨骼祖细胞的长期维持似乎是增加的基础 上面部与下面部直接骨化真皮骨相对于软骨的比例。重要的是 为了公共卫生，许多常见的颅面出生缺陷会影响颅骨的各个部分，包括 颅缝早闭、腭裂和中耳骨异常可能是由性早熟引起的 骨骼祖细胞的分化。该提案中概述的目标采用遗传和发育 斑马鱼和小鼠模型中的方法，结合复杂的实时成像和全基因组 表情分析，以证实这种新的面部模式模型。拟议的实验将建立 从她广泛的初步数据中检验了关键分化的两个新目标的假设- 抑制锯齿状缺口通路 - 成纤维细胞生长因子 20（目标 1）和核受体 2f 基因 （目标 2 和 3）——积极维持发育胚胎上表面的细胞处于祖细胞状态，从而 以牺牲上面部骨骼的软骨分化为代价来保留真皮骨前体。目标 1和3将在博士的指导下启动。 Crump 和 Chai 在 R00 时期完成， 而目标 2 则更进一步，将在 K99 阶段结束之前完成。 该项目旨在促进莫克博士获得终身教职的职业目标 顶尖学术研究机构的助理教授。她计划开展一项独立研究 该计划依靠斑马鱼和小鼠模型中最先进的遗传和成像方法 解决与人类健康明显相关的颅面发育生物学中未解决的问题。 在 K99 阶段，她将受益于 Crump 博士对斑马鱼发育的持续指导， 她的合作导师杨柴博士提供了小鼠颅面生物学方面的重要培训，以及其他职业和 在与她的全体咨询委员会定期举行的会议上提供科学指导。额外职业 南加州大学的发展活动，例如资助写作和指导研讨会，将为莫克博士做好准备 在 R00 阶段过渡到独立教职职位。作为南加州大学主办的最有经验的大学之一 以及该国蓬勃发展的颅面和骨骼生物学家社区，没有比这更好的地方了 她可以获得所需的培训、资源和合作者网络，以将自己打造成一名 颅面生物学独立研究者。