Mechanisms of FoxJ1 in tooth morphogenesis

首席调查员/项目主任(最后、第一、中间)： 说明：请参阅说明。说明应用程序的广泛、长期目标和具体目标，并提及与健康相关的 项目(即与该机构使命的相关性)。简明扼要地描述实现这些目标的研究设计和方法。描述 你将用来追求这些目标的基本原理和技术。 此外，用两三句简单明了的话描述这项研究与公共卫生的相关性。如果应用程序得到资助，则此 原样的描述将成为公开信息。因此，不包括专有/机密信息。不要超过空格 但前提是。 近年来，人们发现了许多与牙齿形态发生有关的新基因。 尽管在识别新的基因和信号机制方面取得了很大进展，但 调控牙齿发育的形态发生阶段已经有文献记载，转录 成牙本质细胞和成釉细胞的细胞分化调控机制目前知之甚少。 更好地理解这一过程的机制方面是必要的，而不仅仅是为了理解正常 牙齿的形态发生，还能让牙齿再生，最终能够更好地发育和交付 治疗策略。我们实验室发现FoxJ1是一种新的参与牙齿晚期的转录因子 和头面部的形态发生。FoxJ1(也称为HFH-4，FHKL-13)属于叉头家族 已知含有叉头(也称为有翼螺旋)dna结合域的基因可以调节 通过细胞命运决定发育。我们的初步数据显示FoxJ1在小鼠磨牙中表达 E18.5开始的内牙上皮及新生期前成釉细胞和成牙本质细胞 在E17.5和E17.5期间，口腔上皮和颌下腺中也有表达。 新生儿出生第一天。我们的瞬时转染数据表明FoxJ1被激活，也被物理激活 与PITX2相互作用，PITX2是参与颅面/牙齿早期发育的同源盒转录因子基因。 这项提议的总体目标是检验我们的假设，即FoxJ1在脑胶质瘤的细胞分化中发挥作用。 利用小鼠遗传学研究牙齿发育过程中的成釉细胞和成牙本质细胞。我们将检验我们的假设 在牙齿发育过程中，PITX2与其他转录因子共同调节FoxJ1的表达。 此外，FoxJ1与PITX2在物理上相互作用，并以正反馈的方式自动调节其启动子 时尚。我们将检验我们的假设，即FoxJ1与PITX2和其他牙齿特异转录相互作用 牙齿发育的钟声晚期和分泌前期调控因子：新基因的鉴定 参与颅面/牙齿发育将增加我们对基本发育的了解 正常胚胎发育所需的程序。了解这些组件如何相互作用以促进 正常的头面部发育将加深我们对遗传缺陷的理解。我们可以的 然后推广抑制严重颅面畸形的方法。 演出现场(S)(组织、市、州) 德克萨斯州A&M健康科学中心，生物科学与技术研究所，休斯顿，德克萨斯州 小灵通398(04/06版)第2页表格第2页

Principal Investigator/Program Director (Last, First, Middle): DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe the rationale and techniques you will use to pursue these goals. In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. In recent years a number of new genes have been identified that are involved in tooth morphogenesis. Though much progress has been made in identifying new genes and the signaling mechanisms that regulate morphogenetic stages of tooth development have been documented, the transcriptional mechanisms that regulate cytodifferentiation of the odontoblasts and ameloblasts are poorly understood. Better understanding of the mechanistic aspect of this process is necessary, not only to understand normal tooth morphogenesis, but also to regenerate teeth, and eventually be able to develop and deliver better therapeutic strategies. Our lab has identified FoxJ1 as a new transcription factor involved in late stage tooth and craniofacial morphogenesis. FoxJ1 (also known as HFH-4, FHKL-13) belongs to the fork-head family of genes, containing a fork-head (also known as winged helix) DNA binding domain is known to regulate development via cell fate determination. Our preliminary data reveals FoxJ1 expression in the mouse molar inner dental epithelium from E18.5 onwards and in the pre-ameloblasts and odontoblasts during neonate day 1. It is also expressed in the oral epithelium and sub-mandibular salivary gland during E17.5 and neonate day 1. Our transient transfection data indicates that FoxJ1 is activated by, and also physically interacts with PITX2, a homeobox transcription factor gene involved in early craniofacial/tooth development. The overall goal of this proposal is to test our hypothesis that FoxJ1 plays a role in cytodifferentiation of ameloblasts and odontoblasts during tooth development using mouse genetics. We will test our hypothesis that PITX2 regulates FoxJ1 expression in concert with other transcription factors during tooth development. Moreover, FoxJ1 physically interacts with PITX2 and auto-regulates its promoter in a positive feed back fashion. We will test our hypothesis that FoxJ1 interacts with PITX2 and other tooth specific transcription factors to regulate late bell and pre-secretory stages of tooth development.The identification of new genes involved in craniofacial/tooth development will increase our knowledge about the basic development programs required for normal embryogenesis. Understanding how these components interact to promote normal craniofacial development will further our understanding of genetic defects. We can then promote methodologies to inhibit severe craniofacial anomalies. PERFORMANCE SITE(S) (organization, city, state) Texas A&M Health Science Center, Institute for Biosciences and Technology, Houston, TX PHS 398 (Rev. 04/06) Page 2 Form Page 2