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成功的，独立的，颅面 开发生物学家，进行以人疾病为中心的可翻译研究，旨在改善 牙科，口服和颅面健康。这个总体目标将通过实施高度实现 协调，透彻和综合的职业发展计划，包括修改指导的组成部分 和培训，熟练的研究环境和一个完整的研究项目。首先，职业 发展计划完成了一个心态，咨询委员会，合作者以及课程和会议 已经建立了为申请人提供过渡到职位的技能和指导 及时独立。威廉姆斯博士是一位成功的资助研究人员，领导者 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，将提供关键的指导和反馈 颅骨，牙齿，搪瓷，细胞培养，生物信息学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教职员工，他们将专门协助 与职业过渡直接相关的组件申请人。此外，生物信息学和 包括有关骨骼和牙齿发育和生物矿化的会议，以促进这些组成部分 培训计划。第二，熟练的研究环境 - 颅面生物学系， 科罗拉多大学以及相关资源，核心设施和教职员工不直接 成立申请人咨询委员会 - 建立旨在保证申请人的成功。 第三，已经提出了一个研究项目，以促进在新生物学领域的申请人培训 对于他的独立道路至关重要，同时保持改善牙齿，口服的关键目标 和颅面健康。这些目标的核心是了解独特的基因调节网络驱动 颅骨骼矿化 - 在中胚层衍生的树干骨骼中很好地描述了一个过程 由于其独特的发育起源，因此缺乏颅骨骨骼的清晰度。为此，研究 提案利用三个目的来检验重要假设，即memo1和runx2基因整合到 驱动关键颅骨结构的矿化，包括牙齿和骨骼。目的我将确定是否 Memo1表达在体内颅内软骨骨化的背景下直接由Runx2调节 和体外取消。 AIM II将更具体地确定Memo1在颅内软骨中的作用 在此过程中，骨化及其与RUNX2-II的遗传整合。最后，AIM III将确定这些角色 分子在牙齿发育过程中发挥了搪瓷层的矿化作用。总的来说，这 全面的职业发展和研究计划将确保申请人成功过渡 从依赖的研究地位到准备充分的独立性之一。