The Role of microRNA-21, 27 and 29 in Tooth Movement

 描述(由候选人提供)：NIDCR颁发的临床科学家指导研究职业发展奖(K08)将为具有牙周学和基础科学培训背景的正畸医生的首席研究员提供机会，获得更多关于microRNA生物学、表观遗传学和药物开发的科学知识和研究培训，并为其研究活动提供保障时间。最近的证据表明，microRNAs通过调控大量的细胞外基质(ECM)基因在组织的发育和重塑中发挥重要作用。正畸牙齿移动是一个复杂的生物学事件，涉及大量ECM基因的协同表达调控，包括压缩侧的一组骨吸收效应基因和张力侧的一组基质合成代谢基因。主要研究人员已经证明，在小鼠模型中，microRNAs在牙齿移动中发挥重要作用，不同的力模式在细胞培养和大鼠模型中诱导不同的microRNA-21、27和29及其靶基因的表达模式。这项研究的假设是，牙周组织中microRNA-21、27和29的表达通过改变ECM基因的表达水平来影响牙齿的移动，导致ECM基因的合成代谢活性增加，新的基质在张力侧沉积，同时伴随着破骨细胞的形成，并降低了压缩侧的骨密度。本研究的具体目的是1)确定和比较miR-21、27和29对二维和三维细胞培养中的牙周关键细胞类型、牙周膜成纤维细胞、成骨细胞和破骨细胞的调节作用以及对机械载荷的响应；2)绘制miR-21、27和29家族在正畸牙移动过程中的时空表达图谱；3)确定miR-21、27和29的模拟物和抑制剂影响大鼠牙齿移动速率的能力。这项职业发展奖将包括授课课程、实验室轮换、研究项目以及世界级调查人员的指导和专业知识。在萨尔瓦多·纳雷斯博士和托马斯·迪克维希博士的指导下，以及来自microRNA生物学、表观遗传学、动物遗传学和生物制药领域的多元化咨询委员会的经验和见解，职业发展奖将确保首席调查员能够继续他的专业发展，实现他成为一名独立调查员的目标。培训将主要在伊利诺伊大学芝加哥分校(UIC)牙科学院举行，并在德克萨斯农工大学、宾夕法尼亚大学和密歇根大学安娜堡分校进行多次实验室轮换，让首席研究员获得研究应用所需的技术和建议方面的技能。这项拟议研究的最终目标是通过促进转译研究和开发一种新的基于microRNA的方法来改善正畸护理，因为主要研究人员将发展成为独立的正畸医生/研究人员。

 DESCRIPTION (provided by candidate): The Mentored Clinical Scientist Research Career Development Award (K08) from NIDCR will provide the principal investigator who is an orthodontist with his background of periodontics and basic science training with the opportunity to receive additional scientific knowledge and research training in microRNA biology, epigenetics and drug development and protected time for his research activities. Recently emerging evidences show that microRNAs play a significant role in the development and remodeling of tissues through the regulation of large sets of extracellular matrix (ECM) genes. Orthodontic tooth movement is a complex biological event that involves the coordinated expression regulation of large sets of ECM genes, including a set of bone resorption effectors on the compression side and a set of matrix anabolic genes on the tension side. The principal investigator has demonstrated that microRNAs play important roles in tooth movement in a mouse model and different modes of forces induce different expression patterns of microRNA-21, 27 and29 as well as their target genes in cell cultures and a rat model. The hypothesis of this proposed research is that microRNA-21, 27 and 29 expression in periodontal tissues affects tooth movement by altering ECM gene expression levels, resulting in increased anabolic activity of ECM genes and new matrix deposition on the tension side in tandem with osteoclastogenesis and decreased bone mineral density on the compression side. The specific aims of this proposed research are 1) To determine and compare the effect of miR-21, 27 and 29 modulation on key periodontal cell types, periodontal ligament fibroblasts, osteoblasts, and osteoclasts, in 2- and 3-dimensional cell cultures and in response to mechanical loading; 2) To map the spatial and temporal expression of miR-21, 27 and 29 family expression during orthodontic tooth movement; 3) To determine the ability of miR-21, 27 and 29 mimics and inhibitors to affect the rate of tooth movement in a rat model. This career development award will involve didactic courses, laboratory rotations, a research project, and the guidance and expertise of world-class investigators. Under the mentorship of Drs. Salvador Nares and Thomas Diekwisch, and the experience and insights of a diverse Advisory Committee from the areas of microRNA biology, epigenetics, animal genetics and biopharmaceutics, the Career Development Award will ensure that the principal investigator can continue his professional development and achieve his goal of becoming an independent investigator. The training will be held mainly at the University of Illinois at Chicago (UIC) College of Dentistry with a number of laboratory rotation sessions at the Texas A&M University, the University of Pennsylvania and the University of Michigan at Ann Arbor for the principal investigator to gain his skills in the techniques and advice required in the research application. The ultimate goal of the proposed research is to improve orthodontic care by contributing to translational research and leading to the development of a novel microRNA-based approach as the principal investigator develops to be an independent orthodontist/ researcher.