Analysis of the Role of Ras Signaling in Amelogenesis

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发挥核心作用。RTKs激活的一个主要途径是Ras/MAPK级联反应。Ras/MAPK通路中的功能获得突变可导致一系列的综合征，称为“Rasopathies”。Costello综合征(CS)是其中之一，是一种罕见的疾病，其特征是多发性颅面、肌肉骨骼、皮肤病和心脏异常，以及不同程度的认知障碍和癌症风险增加。CS是由HRAS中的杂合性新生胚系突变引起的，该突变导致了具有结构性活性的RAS蛋白。CS提供了一个独特的人体模型来研究RAS信号在颅面和牙齿发育中的作用，因此我和我的合作者描述了CS患者的头面部和牙齿的表型。我们发现了一些新的颅面和牙齿畸形；其中最引人注目的是明显的釉质发育不良(釉质变薄)。对CS小鼠模型的牙齿进行组织学检查，发现门牙发育不良，釉质发育不良，成釉细胞(造釉细胞)紊乱。CS小鼠模型中的成釉细胞似乎过度增殖，并表现出极性的丧失。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在成釉细胞分化(釉质形成)和成釉细胞极性中的作用。通过了解釉质形成的机制，我们可以设计出改进的策略来预防、诊断和治疗龋齿和其他釉质缺陷。此外，探讨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。 与公众健康相关：釉质是牙齿坚硬的外层覆盖物，可以防止牙齿腐烂。牙釉质不能再生，目前治疗龋齿的标准方法是牙齿修复。通过了解釉质是如何形成的，我们可以设计出改进的策略来预防、诊断和治疗龋齿和其他釉质缺陷。

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.