Progenitor Regulation in Craniofacial Development and Regeneration

颅面发育和再生中的祖细胞调节

• 批准号: 10783456
• 负责人: Gage D Crump
• 金额: $ 2.69万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-14 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10783456
• 关键词: Adult; Affect; Arthritis; Award; California; Cartilage; Cells; Congenital Abnormality; Development; Disease; Doctor of Philosophy; Economics; Face; Faculty; Fellowship; Fishes; Funding; Future; Genes; Genetic; Genetic Techniques; Goals; Head; Human; Image; Imaging Techniques; Industry; Injury; Jaw; Joints; Knowledge acquisition; Maintenance; Mentors; Microscopy; Modeling; Mus; National Institute of Dental and Craniofacial Research; Natural regeneration; Patients; Pattern; Population; Positioning Attribute; Postdoctoral Fellow; Privatization; Publishing; Regenerative Medicine; Regulation; Research; Research Personnel; Resources; Role; Science; Signal Transduction; Skeleton; Stem Cell Research; Surgical sutures; Technology; Temporomandibular Joint; Universities; Work; Zebrafish; arthropathies; bone; career; craniofacial; craniofacial development; craniofacial repair; craniofacial tissue; cranium; healing; high school; human model; improved; innovation; man; member; notch protein; novel; progenitor; programs; recruit; regenerative; regenerative approach; repaired; skeletal; skeletal disorder; stem cell biology; stem cells; tenure track; underrepresented minority student

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.

头部和面部的先天缺陷在人类中很常见。颅骨损伤和关节疾病， 尤其影响下颌颞下颌关节，是重大的经济和社会负担。这 该提案旨在支持职业中期调查员盖奇·克伦普 (Gage Crump) 博士的上升轨迹，他在 颅面发育和干细胞生物学的界面。具体来说，他开发了强大的新产品 人类颅面出生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，并以大胆的新方向，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、干细胞和再生医学及其创始机构 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. Eli 和 Edythe Broad 干细胞研究中心负责。 安德鲁·麦克马洪（Andrew McMahon）拥有卓越的核心资源，并且最近招募了初级教师。他目前是 三个来自 NIDCR 的 R01，并在 Developmental Cell、eLife、Development 和 PLoS Genetics 涵盖从颅面发育到颌骨修复和关节炎等多种主题 颚。他建立了一支优秀的研究团队，多名学员获得K99和F31奖学金 来自 NIDCR 的奖学金以及著名的私人奖学金。他之前的学员已经获得终身教职 HHMI 资助的实验室中的教师和行业职位以及博士后。他还参加地方和国家 努力招募代表性不足的少数族裔学生从高中到研究生进入干细胞科学领域 水平。这些努力在 2017 年向 Crump 博士颁发的南加州大学指导奖中得到了体现。该研究项目 重点关注祖细胞在构建面部骨骼以及维护和修复面部骨骼中的作用 成人。这些研究利用了斑马鱼独特的遗传和成像优势，结合其 成年后自然再生的能力令人印象深刻。第一个程序使用新的基因编辑技术 在斑马鱼中分析祖细胞调节中新型颅面图案基因的需求，以及 使用延时显微镜直接对祖细胞谱系定型进行成像。正如研究所证明的那样 从鱼到人的锯齿状缺口信号传导，将在小鼠中验证斑马鱼的发现 晚年。第二个项目研究了两种类型关节的基于干细胞的维护： 颅骨和滑膜颌关节的缝合。第三个项目建立在骨、软骨、 和成年斑马鱼颌骨的关节再生，以及基础研究人员的高度协作网络 和南加州大学的临床医生，了解不同类型的内源干细胞如何被激活进行修复 颅面组织。完成这些研究将揭示干细胞之间的共性和差异 构建、维持和修复颅面骨骼的细胞，具有以下方面获得的基础知识： 斑马鱼为未来改善患者骨骼愈合的再生方法提供信息。