Proteomics and Genetics of Enamel and Dentin

遗传性釉质或牙本质缺陷的患者，因为他们的牙齿外观不美观， 缺乏自尊，认为自己的生活质量较低。他们的牙齿很痛： 他们不吃热的食物、冷饮和冰淇淋。一个9岁的牙釉质有缺陷的女孩告诉我们 奶油会疼得像“当你的肘部撞错了”。增进我们对正常和 病理性牙齿形成为改善诊断、治疗、 以及遗传性牙病的治疗。在这项研究中，我们检验了以下三个假设： 1)特殊的釉质和牙本质蛋白编码基因的缺陷会导致成釉。 牙本质发育不全或牙本质发育不良。 2)全基因组搜索和候选基因方法可以有效地识别与 遗传性牙病的病因学。 3)鉴定成釉细胞转录组和釉质和牙本质蛋白质组将识别 对牙釉质和牙本质形成至关重要的蛋白质，并提高我们对分子的理解 正常和病理性牙齿形成的机制。 为了检验这些假设，我们提出了以下两个具体目标： SA 1：识别导致牙釉质和牙本质遗传性缺陷的基因和突变。 SA 2：分离和鉴定发育中细胞外基质中的分子 牙釉质和牙本质。 方法：我们招募非综合征遗传性牙釉质和牙本质缺陷的家系，特征 并对候选基因进行突变分析，以确定其原因。什么时候 我们可能会进行全基因组搜索或联合分析，将一小部分基因组与 牙病。新的候选基因是通过鉴定成釉细胞转录组和 对牙釉质和牙本质细胞外基质进行蛋白质组学分析，这也表征了 蛋白质的结构。 意义：确定导致牙釉质和牙釉质非综合征遗传性缺陷的全套基因 牙本质将改变我们分类、诊断和感知这些疾病的方式。候选人名单 在出现的家族中，可能导致疾病的基因将使用既定的基因型别进行优先排序- 表型相关。随着对有明确突变的人的治疗结果进行评估， 牙釉质或牙本质粘结等手术的成败可能与哪种基因有关 突变，导致治疗计划的改进。未来的基因分析可能会将基因变化 这些基因对龋齿的易感性，并为牙齿形成的机制提供了洞察力。

Patients with inherited enamel or dentin defects, because of the disfiguring appearance of their teeth, have low self-esteem and perceive themselves as having an inferior quality of life. Their teeth are painful: they avoid hot foods, cold drinks and ice cream. One 9-year-old girl with defective enamel told us that ice cream hurts like "when you bump your elbow wrong". Advancing our understanding of normal and pathological tooth formation provides the best long-term hope for improvements in the diagnosis, treatment, and cure of inherited dental diseases. In this study we test the following three Hypotheses: 1) Defects in the genes encoding specialized enamel and dentin proteins cause amelogenesis imperfecta and dentinogenesis imperfecta or dentin dysplasia, respectively. 2) Genome-wide searches and candidate gene approaches can efficiently identify genes involved in the etiology of inherited dental disorders. 3) Characterizing the ameloblast transcriptome and the enamel and dentin proteomes will identify proteins critical for enamel and dentin formation and improve our understanding of the molecular mechanisms of normal and pathologic tooth formation. To test these hypotheses we propose the following two Specific Aims: SA 1: Identify genes and mutations that cause inherited defects of enamel and dentin. SA 2: Isolate and characterize molecules in the extracellular matrices of developing enamel and dentin. Approach: We recruit families with non-syndromic inherited defects of enamel and dentin, characterize their phenotypes, and perform mutation analyses on candidate genes to identify their causes. When possible we will perform genome-wide searches or joined analyses to link a small part of the genome to the dental disease. New candidate genes are identified by characterizing the ameloblast transcriptome and by performing proteomic analyses of the enamel and dentin extracellular matrices, which also characterize the proteins' structures. Significance: Identifying the full set of genes that cause non-syndromic inherited defects of enamel and dentin will change the ways we classify, diagnose, and perceive these disorders. The list of candidate genes that might cause the disease in a presenting family will be prioritized using established genoptype- phenotype correlations. As treatment outcomes are evaluated in persons with defined mutations, the success or failure of procedures such as enamel or dentin bonding may correlate with which gene is mutated, leading to improvements in treatment planning. Future genetic analyses may link genetic changes in these genes to susceptibility for dental caries and provide insights into mechanisms of tooth formation.