Progenitor Regulation in Craniofacial Development and Regeneration

头部和面部的出生缺陷在人类中很常见。颅骨损伤和关节疾病， 特别是影响颌的颞下颌关节的疾病是主要的经济和社会负担。这 该提案是为了支持职业生涯中期的调查员Gage Crump博士的上升轨迹，他在 颅面发育和干细胞生物学的接口。具体来说，他开发了强大的新 人类颅面先天缺陷和疾病的斑马鱼模型，这使他能够解开 常见颅面出生缺陷的发育原因，并在一个大胆的新方向，了解 刺激成人颅骨内源性修复的机制。Crump博士是博士项目主任， 南加州大学的发育、干细胞和再生医学， Eli和Edythe Broad干细胞研究中心的成员，该中心是一个快速发展的研究所，由Dr。 安德鲁麦克马洪与特殊的核心资源和最近招募的初级教师。他目前在PI NIDCR的三个R01，并在Developmental Cell，eLife，Development和 从颅面发育到颌骨修复和关节炎， 下巴.他建立了一支出色的研究团队，有几名学员获得了K99和F31奖学金 来自NIDCR，以及著名的私人奖学金。他以前的实习生已经走上了终身教职的道路 教师和行业职位，以及HHMI资助的实验室的博士后。他还参加地方和国家的活动 努力招募代表性不足的少数民族学生从高中到毕业进入干细胞科学 程度.这些努力反映在2017年授予Crump博士的USC指导奖上。研究计划 的重点是祖细胞的作用，在建立面部骨骼，然后维持和修复它， 成年人这些研究利用了斑马鱼独特的遗传和成像优势， 令人印象深刻的自然再生能力。第一个程序使用新的基因编辑技术 在斑马鱼中，分析在祖先调节中对新颅面模式基因的要求，以及 使用延时显微镜直接成像祖细胞谱系定型。例如， 锯齿状缺口信号从鱼到人，在小鼠中验证斑马鱼发现的努力将在 晚年。第二个项目研究了两种类型关节的干细胞维持， 头骨和滑膜颌关节的缝合处第三个项目建立在骨，软骨， 和关节再生，以及基础研究人员的高度合作网络， 以及南加州大学的临床医生，以了解不同类型的内源性干细胞是如何被激活以修复 颅面组织这些研究的完成将揭示股骨柄之间的共性和差异 细胞，建立，然后维持和修复颅面骨骼，与基础知识， 斑马鱼为未来改善患者骨骼愈合的再生方法提供了信息。

Birth defects of the head and face are common in the human population. Skull injuries and joint disease, in particular affecting the temporomandibular joint of the jaw, are a major economic and societal burden. This proposal is to support the upward trajectory of a mid-career investigator, Dr. Gage Crump, who works at the interface of craniofacial development and stem cell biology. Specifically, he has developed powerful new zebrafish models of human craniofacial birth defects and disease, which are allowing him to unravel the developmental causes of common craniofacial birth defects and, in a bold new direction, to understand mechanisms of stimulating endogenous repair of the adult skull. Dr. Crump is Director of the PhD Program in Development, Stem Cells, and Regenerative Medicine at the University of Southern California and a founding member of the Eli and Edythe Broad Center for Stem Cell Research, a rapidly growing institute directed by Dr. Andrew McMahon with exceptional core resources and recently recruited junior faculty. He is currently PI on three R01's from NIDCR and has published featured articles in Developmental Cell, eLife, Development, and PLoS Genetics on diverse topics ranging from craniofacial development to jawbone repair and arthritis of the jaw. He has built up an exceptional research team, with several trainees receiving K99 and F31 fellowships from NIDCR, as well as prestigious private fellowships. His previous trainees have gone on to tenure-track faculty and industry positions, and postdocs in HHMI-funded labs. He also participates in local and national efforts to recruit under-represented minority students into stem cell science from high school to graduate levels. These efforts are reflected by a USC Mentoring Award to Dr. Crump in 2017. The research program focuses on the roles of progenitor cells in building the facial skeleton and then maintaining and repairing it in the adult. These studies exploit the unique genetic and imaging strengths of zebrafish, combined with its impressive capabilities of natural regeneration as adults. The first program uses new gene editing technology in zebrafish to analyse requirements for novel craniofacial patterning genes in progenitor regulation, as well as to directly image progenitor lineage commitment using time-lapse microscopy. As exemplified by studies of Jagged-Notch signaling from fish to man, efforts to validate zebrafish findings in mouse will be performed in latter years. The second program investigates the stem cell-based maintenance of two types of joints, the sutures of the skull and the synovial jaw joint. The third program builds on innovative models of bone, cartilage, and joint regeneration in the adult zebrafish jaw, as well as a highly collaborative network of basic researchers and clinicians at USC, to understand how different types of endogenous stem cells are activated to repair craniofacial tissues. Completion of these studies will reveal commonalities and differences between the stem cells that build and then maintain and repair the craniofacial skeleton, with foundational knowledge acquired in zebrafish informing future regenerative approaches towards improving skeletal healing in patients.