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.

项目摘要 长时间的祖细胞维护雕刻上面 尽管已知数十个基因参与塑造面部骨架，但面部骨骼前体如何 在面部的不同部位分配给软骨与骨骼命运不同 理解齿。 Mork博士在加州大学Gage Crump博士实验室的博士后作品提供了有关如何如何 建立了脊椎动物头骨，骨骼祖细胞的长时间维持似乎是增加的 直接分配的真皮骨相对于上部与下部的软骨相对于软骨的比例。重要的是 对于公共卫生，许多影响头骨各个部位的常见颅面出生缺陷，包括 颅突，裂口和中耳骨异常可能会通过早熟来解释 骨骼祖细胞的分化。该提案中概述的目的采用遗传和发展 斑马鱼和小鼠模型中的方法，结合精致的实物和全基因组的结合 表达分析，以证实这种新的面部图案模型。拟议的实验将建立 从她广泛的初步数据来检验以下假设：关键分化的两个新目标 - 抑制锯齿状 - 核途径 - 成纤维细胞生长因子20（AIM 1）和核受体2F基因 （目标2和3） - 在发育中的胚胎的上面积极维护细胞处于祖细胞状态 在上部面部骨骼中以软骨分化为代价保留皮肤骨前体。目标 1和3将根据Drs的精神制定。 Crump和Chai并在R00期间完成， 而AIM 2则是更远的，并且将在K99阶段结束之前完成。 该项目旨在促进莫克博士的职业目标，即获得终身制的职位 顶级学术研究机构的助理教授。她计划开发一项独立的研究 依赖于斑马鱼和小鼠模型中最先进的遗传和成像方法的程序 解决颅面发育生物学中未解决的问题，与人类健康明显相关。 在K99阶段，她将受益于Crump博士在斑马鱼发展中的持续心态， 从她的同事Yang Chai博士和其他职业和其他职业和其他职业和 定期与她的完整咨询委员会会议的科学指导。额外的职业 USC的开发活动，例如赠款和心态研讨会，将为Mork博士做好准备 在R00阶段过渡到独立的教师职位。作为美国南加州大学拥有最有经验的人之一 以及该国颅面和骨骼生物学家的繁荣社区，几乎没有更好的地方 她可以获取需要确立自己作为一个合作者的培训，资源和网络 颅面生物学的独立研究者。