The Genetic Basis of Human Tooth Agenesis

人类牙齿发育不全的遗传基础

• 批准号: 6856850
• 负责人: SYLVIA A FRAZIER-BOWERS
• 金额: $ 10.36万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6856850
• 关键词: bone morphogenetic proteins; clinical research; congenital dentition disorder; craniofacial; dental development; dental research; dental structure; developmental genetics; family genetics; gene mutation; genetic screening; genome; human subject; linkage mapping; orthodontics; patient oriented research; polymerase chain reaction; tooth loss

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.

描述（由申请人提供）：Sylvia A. Frazier-Bowers博士正在申请新的K23指导研究赠款，以发展为独立的面向患者的临床研究者的职业。 此处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，并促进她的发展成为对颅面综合体人类遗传学的合格研究者。 该提案的目标是发展候选人在对先天缺失的牙齿（牙齿性牙齿）遗传基础进行原始和重要研究方面的专业知识，这是与正畸领域非常相关的领域。 尽管在人类和小鼠中使用遗传和分子方法最近进步，但对与人牙齿发育的基因知之甚少。 确定牙齿性发育不全的分子基础对于研究者对该缺陷的发病机理的理解至关重要，并将为改善治疗方式提供基础。 已经鉴定出两个基因MSX1和PAX9中的突变与非综合性家族性牙齿发育。 具体而言，在他们的实验室中的研究导致发现PAX9中的插入突变会导致摩尔寡头。 随后，他们确定了另外两个负责摩尔寡头的新型突变。基于这些研究，他们假设牙齿发生牙齿是由参与牙齿发育的基因突变引起的，尤其是MSX1和PAX9。这项研究的长期目标是阐明人类牙齿发育的遗传病因。 AIM 1将识别，临床表征并收集来自多个成员的个人和/或家庭的样本 先天缺失的牙齿的模式。他们将通过持续的筛选工作扩大他们最近建立的134个人数据库，并横向扩展当前确定的个体的血统。将从这些家族收集的血液或颊细胞样品中收获DNA。 AIM 2建议使用收集的样品来鉴定与摩尔寡头相关的MSX1和PAX9突变，通过对28例受摩尔寡头型摩尔寡头的患者进行测序。这些研究将有助于确定这两个基因是否负责大多数摩尔寡头病例，还是其他关键候选基因（例如LEF1或BMP4）在某些情况下负责。 AIM 3将利用全基因组筛选来确定基因的染色体位置，从而导致非综合性下颌切牙性发育不全。 AIM 4提议在AIM 3中鉴定出的染色体区域中筛选候选基因，以确定下颌骨发育不全的原因。因此，在此处提出的确定牙齿发育不全的特定模式的遗传基础对可能的牙齿丧失和遗传损失的治疗具有重要意义。这项研究对于申请人的职业目标至关重要，申请人的职业目标是执行与识别导致正畸问题的遗传因素有关的独立和原始研究。