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

 描述（由候选人提供）：NIDCR的指导临床科学家研究职业发展奖（K 08）将为具有牙周病学和基础科学培训背景的牙周病学家提供主要研究者，使其有机会获得microRNA生物学，表观遗传学和药物开发方面的额外科学知识和研究培训，并保护其研究活动的时间。最近出现的证据表明，微小RNA通过调节大量细胞外基质（ECM）基因在组织的发育和重塑中发挥着重要作用。正畸牙齿移动是一个复杂的生物学事件，涉及大量ECM基因的协调表达调控，包括一组压缩侧的骨吸收效应子和一组张力侧的基质合成代谢基因。主要研究者已经证明microRNA在小鼠模型中的牙齿移动中起重要作用，并且不同的力模式诱导microRNA-21，27和29以及它们的靶基因在细胞培养物和大鼠模型中的不同表达模式。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基因表达水平来影响牙齿移动，导致ECM基因的合成代谢活性增加，张力侧的新基质沉积与破骨细胞生成和压缩侧的骨密度降低。本研究的具体目的是：1）确定和比较miR-21、27和29在二维和三维细胞培养中以及在机械负荷下对关键牙周细胞类型、牙周膜成纤维细胞、成骨细胞和破骨细胞的调节作用; 2）研究miR-21、27和29家族在正畸牙移动过程中的时空表达; 3）确定miR-21、27和29模拟物和抑制剂影响大鼠模型中牙齿移动速率的能力。这个职业发展奖将涉及教学课程，实验室轮换，研究项目，以及世界一流的研究人员的指导和专业知识。在萨尔瓦多纳雷斯和托马斯Diekwisch博士的指导下，以及来自microRNA生物学，表观遗传学，动物遗传学和生物药剂学领域的多元化咨询委员会的经验和见解，职业发展奖将确保主要研究者能够继续他的专业发展，并实现他成为独立研究者的目标。培训将主要在伊利诺伊大学芝加哥分校（UIC）牙科学院进行，并在德克萨斯A&M大学、宾夕法尼亚大学和密歇根大学安阿伯分校进行多次实验室轮换，以使主要研究者获得研究申请所需的技术和建议方面的技能。拟议研究的最终目标是通过促进转化研究并导致开发一种新的基于microRNA的方法来改善正畸护理，因为主要研究者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.