Understanding the interaction of Memo1 and Runx2 in craniodental mineralization

了解 Memo1 和 Runx2 在颅齿矿化中的相互作用

• 批准号: 10063988
• 负责人: Eric Van Otterloo
• 金额: $ 24.6万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063988
• 关键词: Advisory Committees; Affect; Ameloblasts; Amelogenesis; Area; Automobile Driving; Binding; Bioinformatics; Biology; Blood Vessels; CBFB gene; Career Mobility; Cartilage; Cell Culture Techniques; Cell Line; Cell Lineage; Cells; Cephalic; ChIP-seq; Colorado; Complement; Complex; Core Facility; DNA Binding; Data Set; Defect; Dental; Dental Enamel; Development; Development Plans; ERBB2 gene; Ectoderm; Embryo; Embryonic Development; Ensure; Enterobacteria phage P1 Cre recombinase; Environment; Face; Faculty; Feedback; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Diseases; Goals; Head; Health; Human; In Vitro; Knowledge; Lead; Mediator of activation protein; Mentors; Mesoderm; Minerals; Modeling; Molecular; Neural Crest Cell; Oral; Osteoblasts; Osteogenesis; Pathology; Patients; Phenotype; Physiologic Ossification; Physiologic calcification; Play; Positioning Attribute; Process; Protein Isoforms; Regulator Genes; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; Resources; Role; Skeleton; Structure; Testing; Time; Tissues; Tooth structure; Training; Training Programs; Universities; Work; base; biomineralization; bone; career development; cell motility; craniofacial; craniofacial complex; craniofacial tissue; cranium; developmental disease; gene function; human disease; improved; in silico; in vivo; insight; member; mineralization; mutant; novel; oral ectoderm; post-doctoral training; prevent; promoter; research and development; skeletal; skills; skull base; stem; success; symposium; tissue regeneration; transcription factor; transcriptome sequencing

The long-term goals of the applicant are to become a successfully funded, independent, craniofacial developmental biologist, conducting human-disease-focused and translatable research aimed at improving dental, oral, and craniofacial health. This overarching goal will be actualized by the implementation of a highly coordinated, thorough, and integrated career development plan including components of mentored guidance and training, an adept research environment, and a complementary research project. First, a career development plan comprised of a mentor, advisory committee, collaborators, and courses and conferences has been established to provide the applicant with the skills and guidance to transition into a position of independence in a timely manner. The mentor, Dr. Williams, is a successfully funded researcher and leading expert in craniofacial biology and is thus well suited to oversee the applicant’s training. The advisory committee includes both internal and external members that will provide critical guidance and feedback on aspects of career development and technical components of cranial bone, tooth, enamel, cell culture, bioinformatic, and gene-editing biology. The committee also includes two young faculty members who will specifically assist the applicant in components directly related to career transition. In addition, courses in bioinformatics and conferences on bone and tooth development and biomineralization are included to facilitate these components of the training program. Second, an adept research environment – the Department of Craniofacial Biology, the University of Colorado, along with associated resources, core facilities, and faculty members not directly involved in the applicant’s advisory committee – is established to provide assurance of the applicant’s success. Third, a research project has been proposed to facilitate training of the applicant in new areas of biology essential for his path to independence while simultaneously maintaining the key goals of improving dental, oral, and craniofacial health. Central to these goals are understanding the unique gene regulatory networks driving cranial skeletal mineralization – a process that is well described in the mesoderm-derived trunk skeleton yet lacks clarity in the cranial skeleton owing to its unique developmental origins. To this end, the research proposal utilizes three aims to test the important hypothesis that Memo1 and Runx2 genetically integrate to drive mineralization of key craniodental structures, including teeth and bones. Aim I will establish whether Memo1 expression is directly regulated by RUNX2 in the context of in vivo cranial endochondral ossification and in vitro amelogenesis. Aim II will more specifically determine the role of MEMO1 in cranial endochondral ossification and its genetic integration with Runx2-II in this process. Finally, Aim III will establish the role these molecules play in mineralization of the enamel layer during tooth development. Collectively, this comprehensive career development and research plan will ensure the successful transition of the applicant from a dependent research position into one of well-prepared independence.

申请人的长期目标是成为一名成功资助的、独立的、颅面 发育生物学家，进行以人类疾病为中心的可转化研究，旨在改善 牙齿、口腔和颅面健康。这一总体目标将通过实施高度 协调、彻底和综合的职业发展计划，包括指导性指导的组成部分 和培训、熟练的研究环境和互补的研究项目。首先，职业生涯 发展计划由导师、咨询委员会、合作者以及课程和会议组成 已成立，旨在为申请人提供过渡到职位的技能和指导 及时独立。导师威廉姆斯博士是一位成功资助的研究员和领导 颅面生物学专家，因此非常适合监督申请人的培训。咨询委员会 包括内部和外部成员，他们将就各方面提供关键指导和反馈 颅骨、牙齿、牙釉质、细胞培养、生物信息学等的职业发展和技术组成部分 基因编辑生物学。该委员会还包括两名年轻的教职人员，他们将专门协助 与职业转型直接相关的申请人。此外，还有生物信息学和 包括关于骨骼和牙齿发育以及生物矿化的会议，以促进这些组成部分 的培训计划。其次，良好的研究环境——颅面生物学系、 科罗拉多大学，以及非直接相关的资源、核心设施和教职人员 参与申请人的咨询委员会——成立是为了确保申请人的成功。 第三，提出了一个研究项目，以促进申请人在生物学新领域的培训 这对于他走向独立之路至关重要，同时保持改善牙科、口腔、 和颅面健康。这些目标的核心是了解独特的基因调控网络驱动 颅骨骨骼矿化——这一过程在中胚层衍生的躯干骨骼中得到了很好的描述 由于其独特的发育起源，颅骨骨骼缺乏清晰度。为此，研究 该提案利用三个目标来检验 Memo1 和 Runx2 基因整合的重要假设 促进关键颅齿结构（包括牙齿和骨骼）的矿化。目标 我将确定是否 Memo1 表达在体内颅骨软骨内骨化过程中受 RUNX2 直接调节 和体外釉质形成。目标 II 将更具体地确定 MEMO1 在颅骨软骨内的作用 骨化及其在此过程中与 Runx2-II 的遗传整合。最后，目标 III 将确定这些角色 在牙齿发育过程中，分子在牙釉质层的矿化中发挥作用。总的来说，这 全面的职业发展和研究计划将确保申请人的成功过渡 从依赖的研究职位转变为准备充分的独立研究职位。