The Genetic Basis of Human Tooth Agenesis

描述(由申请人提供)：Sylvia A.Frazier-Bowers博士正在申请一项新的K23指导研究拨款，以发展其作为一名独立的以患者为导向的临床研究员的职业生涯。这里描述的研究和职业发展计划将结合Frazier-Bowers博士在正畸和遗传学方面的培训，并促进她发展成为一名称职的颅面复合体人类遗传学研究员。这项建议的目的是发展候选人的专业知识，对先天性缺失牙齿(牙齿发育不全)的遗传基础进行原创性和重要的研究，这是一个与正畸领域非常相关的领域。尽管最近在人类和老鼠身上利用遗传和分子方法取得了进展，但人们对参与人类牙齿发育不全的基因知之甚少。确定牙齿发育不全的分子基础对于研究人员了解这种缺陷的发病机制至关重要，并将为改进治疗方式提供基础。两个基因Msx1和PAX9的突变已被发现与非综合征家族性牙齿发育不全有关。具体地说，他们实验室的研究发现，PAX9的插入突变会导致磨牙缺牙。他们随后又发现了两个与磨牙缺失有关的新突变。基于这些研究，他们假设牙齿发育不全是由参与牙齿发育的基因突变引起的，特别是Msx1和PAX9。这项研究的长期目标是阐明人类牙齿发育不全的遗传病因。目标1将从具有多个成员的个人和/或家庭中识别、临床特征和收集样本 先天缺牙的图案。他们将通过持续的筛查工作和横向扩展目前确定的个人的谱系，扩大他们最近建立的134人的数据库。DNA将从从这些家庭收集的血液或口腔细胞样本中提取。目的2利用收集的样本对28例磨牙缺失患者的Msx1和PAX9基因进行测序，以确定这些突变与磨牙缺失相关。这些研究将有助于确定这两个基因是否与大多数磨牙缺失病例有关，或者是否其他关键候选基因，如LEF1或BMP4在某些病例中起作用。AIM 3将利用全基因组筛查来确定导致非综合征性下颌切牙发育不全的基因的染色体位置。目的4建议筛选目的3中确定的染色体区域的候选基因，以确定下颌切牙发育不全的原因。因此，确定牙齿发育不全的特定模式的遗传基础对于后天性和遗传性牙齿缺失的可能治疗具有重要意义。这项研究是申请者职业目标的核心，该目标是进行与识别导致正畸问题的遗传因素相关的独立和原创性研究。

DESCRIPTION (provided by applicant): Dr. Sylvia A. Frazier-Bowers is applying for a new K23 mentored research grant to develop a career as an independent patient-oriented clinical investigator. The research and career development plans described here will combine Dr. Frazier-Bowers' training in orthodontics and genetics and facilitate her development into a competent investigator of the human genetics of the craniofacial complex. The objectives of this proposal are to develop the candidate's expertise in conducting original and significant research of the genetic basis of congenitally missing teeth (tooth agenesis), an area of great relevance to the field of orthodontics. Despite recent advances using genetic and molecular approaches in humans and mice, little is known about the genes involved in human tooth agenesis. Determining the molecular basis for tooth agenesis is critical to the investigator's understanding of the pathogenesis of this defect, and will provide the basis for improved treatment modalities. Mutations in two genes, MSX1 and PAX9, have been identified in association with non-syndromic familial tooth agenesis. Specifically, studies in their laboratory led to the discovery that an insertion mutation in PAX9 causes molar oligodontia. They have subsequently identified two more novel mutations responsible for molar oligodontia. Based on these studies, they hypothesize that tooth agenesis arises from mutations in genes involved in tooth development, particularly MSX1 and PAX9. The long-term goals of this research are to elucidate the genetic etiology of human tooth agenesis. Aim 1 will identify, clinically characterize, and collect samples from individuals and/or families with multiple members demonstrating patterns of congenitally missing teeth. They will expand their recently established database of 134 individuals through continual screening efforts and by laterally extending the pedigrees of individuals currently identified. DNA will be harvested from blood or buccal cell samples collected from these families. Aim 2 proposes to use the collected samples to identify MSX1 and PAX9 mutations associated with molar oligodontia by sequencing these genes in 28 patients affected with molar oligodontia. These studies will help to determine if these two genes are responsible for the majority of cases of molar oligodontia, or if other key candidate genes such as LEF1, or BMP4 are responsible in some cases. Aim 3 will utilize a genome-wide screen to determine the chromosomal location of the gene causing non-syndromic mandibular incisor agenesis. Aim 4 proposes to screen candidate genes in the chromosomal region identified in Aim 3 to determine the cause of mandibular incisor agenesis. Thus, determining the genetic basis of specific patterns of tooth agenesis as proposed here has significant implications for the possible treatment of both acquired and inherited loss of teeth. This research is central to the career goals of the applicant, which are to perform independent and original research that is relevant to identifying genetic factors that lead to orthodontic problems.