Proteomics and Genetics of Enamel and Dentin

牙釉质和牙本质的蛋白质组学和遗传学

• 批准号: 7779056
• 负责人: JAMES P SIMMER
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-13 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7779056
• 关键词: 9 year old; Abbreviations; Ameloblasts; Amelogenesis Imperfecta; Appearance; Binding; Biological Process; Blast Cell; Candidate Disease Gene; DSPP gene; Defect; Dental; Dental Caries Susceptibility; Dental Enamel; Dentin; Dentin Dysplasia; Dentin Formation; Dentinogenesis Imperfecta; Diagnosis; Disease; Elbow; Etiology; Extracellular Matrix; Failure; Family; Food; Future; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genome; Glycoproteins; Grant; Hereditary Disease; Hyaluronan; Ice Cream; Inferior; Inherited; Length; Link; MMP-20; Molecular; Mutate; Mutation; Pain; Participant; Pathologic; Patients; Persons; Phenotype; Phosphoproteins; Play; Post-Translational Protein Processing; Procedures; Process; Proteins; Proteoglycan; Proteome; Proteomics; Publications; Quality of life; Recruitment Activity; Reporting; Research; Role; Testing; Tooth Diseases; Tooth structure; Treatment outcome; amelogenin; dentin sialoprotein; dimer; drinking; enamelin; genetic analysis; genome-wide; girls; improved; insight; kallikrein 4; malformation; member; protein structure; public health relevance; self esteem; success; treatment planning

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: There is a group of specialized genes that are required to make the dentin and enamel layers of our teeth. Mutations that interfere with the normal expression of these genes cause disfiguring, painful, malformations of the teeth. The objective of our research is to identify these genes and to determine their function. Accomplishing the proposed study will improve the understanding and management of inherited dental defects.

描述（由申请人提供）：患有遗传性牙釉质或牙本质缺陷的患者，由于牙齿外观毁容，自尊心低，认为自己的生活质量较差。他们的牙齿疼痛：他们不吃热的食物、冷饮和冰淇淋。一个牙釉质有缺陷的9岁女孩告诉我们，吃冰淇淋就像“撞错了肘部”一样疼。提高我们对正常和病理牙齿形成的理解，为改善遗传性牙病的诊断、治疗和治愈提供了最好的长期希望。在本研究中，我们检验了以下三个假设：1)编码珐琅质和牙本质特异性蛋白的基因缺陷分别导致无淀粉性发育不全和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病因相关的基因。3)表征成釉细胞转录组和牙釉质和牙本质蛋白质组将识别牙釉质和牙本质形成的关键蛋白质，并提高我们对正常和病理牙齿形成的分子机制的理解。为了验证这些假设，我们提出以下两个具体目标：SA 1：确定导致牙釉质和牙本质遗传缺陷的基因和突变。sa2：分离和表征发育中的牙釉质和牙本质细胞外基质中的分子。方法：我们招募具有非综合征性牙釉质和牙本质遗传缺陷的家庭，对其表型进行表征，并对候选基因进行突变分析以确定其原因。如果可能，我们将进行全基因组搜索或联合分析，以将基因组的一小部分与牙病联系起来。通过表征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，确定了新的候选基因，这也表征了蛋白质的结构。意义：发现导致牙釉质和牙本质非综合征性遗传缺陷的全套基因将改变我们对这些疾病的分类、诊断和认知方式。将使用已建立的基因型-表型相关性对可能导致呈递家族疾病的候选基因列表进行优先排序。由于对具有明确突变的人的治疗结果进行评估，牙釉质或牙本质结合等程序的成功或失败可能与基因突变有关，从而导致治疗计划的改进。未来的遗传分析可能会将这些基因的遗传变化与蛀牙的易感性联系起来，并为牙齿形成的机制提供见解。