Understanding the interaction of Memo1 and Runx2 in craniodental mineralization

申请者的长期目标是成为一个成功资助的、独立的、颅面外科医生。 发展生物学家，进行以人类疾病为重点的可翻译研究，旨在改善 牙科、口腔和颅面健康。这一总体目标将通过实施高度的 协调、全面和综合的职业发展计划，包括指导指导的组成部分 和培训，一个熟练的研究环境，和一个互补的研究项目。第一，事业 由导师、咨询委员会、合作者以及课程和会议组成的发展计划 已经建立，为申请人提供技能和指导，以过渡到 及时实现独立自主。导师威廉姆斯博士是一位成功资助的研究人员和领先的 他是头面部生物学方面的专家，因此非常适合监督申请者的培训。咨询委员会 包括内部和外部成员，他们将就以下方面提供批判性指导和反馈 颅骨、牙齿、釉质、细胞培养、生物信息学和 基因编辑生物学。该委员会还包括两名年轻的教职员工，他们将专门协助 应聘者在与职业转变直接相关的部分。此外，生物信息学和 包括关于骨骼和牙齿发育和生物矿化的会议，以促进这些组件 培训计划的一部分。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，不是直接 参与申请人的咨询委员会--是为申请人的成功提供保证而设立的。 第三，已经提出了一个研究项目，以促进对申请者进行新的生物学领域的培训 对他的独立之路至关重要，同时保持提高牙科，口腔， 和头面部健康。这些目标的核心是理解独特的基因调控网络 颅骨矿化--这一过程在中胚层衍生的躯干骨架中得到了很好的描述 由于其独特的发育起源，颅骨缺乏清晰度。为此，这项研究 Proposal利用三个目标来检验Memo1和Runx2基因整合的重要假设 推动关键的头骨结构矿化，包括牙齿和骨骼。Aim我将确定是否 在活体颅骨软骨内骨化过程中RUNX2直接调节Memo1的表达 和体外成釉作用。AIM II将更具体地确定MEMO1在颅骨内软骨中的作用 骨化及其与Runx2-II在这一过程中的基因整合。最后，AIM III将确立这些角色 在牙齿发育过程中，分子在釉质层的矿化过程中发挥作用。总而言之，这 全面的职业发展和研究计划将确保申请者成功过渡 从一个独立的研究岗位转变为一个准备充分的独立岗位。

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.