Analysis of the Role of Ras Signaling in Amelogenesis

Ras 信号传导在釉质形成中的作用分析

• 批准号: 8201567
• 负责人: Alice Fitzgerald Goodwin
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201567
• 关键词: Affect; Ameloblasts; Amelogenesis; Apoptosis; Biochemistry; Biological Assay; Bromodeoxyuridine; Cardiac; Cell Polarity; Cell model; Cells; Chimeric Proteins; Costello syndrome; Data; Defect; Dental; Dental Enamel; Dental Enamel Hypoplasia; Dental caries; Development; Diagnosis; Employee Strikes; Enamel Formation; Epithelial Cells; Germ-Line Mutation; Goals; HRAS gene; Histology; Human; Immunohistochemistry; Impaired cognition; In Situ Nick-End Labeling; In Vitro; Incisor; MEK inhibition; MEKs; Measures; Mitogen-Activated Protein Kinases; Modeling; Morphology; Mus; Musculoskeletal; Natural regeneration; Odontogenesis; PI3K/AKT; Pathway interactions; Patients; Phenotype; Phosphorylation; Play; Proteins; Proto-Oncogene Proteins c-akt; Rare Diseases; Receptor Protein-Tyrosine Kinases; Role; Sampling; Scanning Electron Microscopy; Signal Pathway; Signal Transduction; Staining method; Stains; Syndrome; TIAM1 gene; Testing; Tooth structure; Western Blotting; amelogenin; cancer risk; craniofacial; enamel matrix proteins; gain of function mutation; improved; inhibitor/antagonist; knock-down; mouse model; novel; prevent; protein expression; protein transport; ras Proteins; restorative dentistry; standard care; trafficking

DESCRIPTION (provided by applicant): Receptor tyrosine kinase (RTK) signaling pathways are known to play a central role in tooth development. A principal pathway activated by RTKs is the Ras/Mitogen-Activated Protein Kinase (MAPK) cascade. Gain-of- function mutations in the Ras/MAPK pathway can cause a number of syndromes, termed "Rasopathies". One of these syndromes is Costello Syndrome (CS), which is a rare disorder characterized by multiple craniofacial, musculoskeletal, dermatological and cardiac anomalies, as well as a varying degree of cognitive impairment and increased risk of cancer development. CS is caused by a heterozygous de novo germline mutation in HRAS that results in a constitutively active Ras protein. CS provides a unique human model to study the role of Ras signaling in craniofacial and dental development, and so my collaborators and I characterized the craniofacial and dental phenotype of CS patients. We identified a number of novel craniofacial and dental anomalies; most striking among these was a pronounced enamel hypoplasia (thinning of the enamel). Histological examination of the teeth from a CS mouse model revealed abnormal incisors with hypoplastic enamel and disorganized ameloblasts (enamel-producing cells). The ameloblasts in the CS mouse model appear to be hyperproliferative and show a loss of polarity. I propose to utilize the CS mouse model as well as in vitro CS cell models to determine the effect of activated Ras signaling on ameloblasts. Ultimately, my goal is to understand the role of Ras in amelogenesis (enamel formation) and ameloblast cell polarity. By understanding the mechanism of enamel formation, we can devise improved strategies to prevent, diagnose and treat cavities and other enamel defects. In addition, exploring the effect of Ras on ameloblast cell polarity will further reveal the general role of Ras in epithelial cell polarity. PUBLIC HEALTH RELEVANCE: Enamel is the hard outer covering of teeth that protects them from decay. Enamel cannot be regenerated, and the current standard treatment of dental decay is dental restoration. By understanding how enamel forms, we can devise improved strategies to prevent, diagnose and treat cavities and other enamel defects.

描述（由申请人提供）：受体酪氨酸激酶（RTK）信号通路已知在牙齿发育中起核心作用。rtk激活的主要途径是Ras/丝裂原活化蛋白激酶（MAPK）级联。Ras/MAPK通路的功能获得突变可引起许多综合征，称为“Rasopathies”。其中一种综合征是Costello综合征（CS），这是一种罕见的疾病，其特征是多发性颅面、肌肉骨骼、皮肤和心脏异常，以及不同程度的认知障碍和癌症发展的风险增加。CS是由HRAS的杂合新生种系突变引起的，该突变导致Ras蛋白构成活性。CS提供了一个独特的人类模型来研究Ras信号在颅面和牙齿发育中的作用，因此我和我的合作者表征了CS患者的颅面和牙齿表型。我们发现了一些新的颅面和牙齿异常；其中最显著的是牙釉质发育不全（牙釉质变薄）。CS小鼠模型的组织学检查显示门牙异常，牙釉质发育不全，成釉细胞（产生牙釉质的细胞）紊乱。CS小鼠模型中的成釉细胞表现出过度增殖和极性丧失。我建议利用CS小鼠模型和体外CS细胞模型来确定激活的Ras信号对成釉细胞的影响。最终，我的目标是了解Ras在成釉发生（牙釉质形成）和成釉细胞极性中的作用。通过了解牙釉质形成的机制，我们可以制定更好的策略来预防、诊断和治疗蛀牙和其他牙釉质缺陷。此外，探索Ras对成釉细胞极性的影响将进一步揭示Ras在上皮细胞极性中的一般作用。