Analysis of the Role of Ras Signaling in Amelogenesis

描述（由申请人提供）：已知受体酪氨酸激酶（RTK）信号通路在牙齿发育中起核心作用。由RTK激活的主要途径是Ras/促分裂原活化蛋白激酶（MAPK）级联。Ras/MAPK途径中的功能获得突变可导致多种综合征，称为“Ras病”。这些综合征之一是科斯特洛综合征（CS），这是一种罕见的疾病，其特征是多种颅面，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中的杂合从头生殖系突变引起的，其导致组成型活性Ras蛋白。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描述了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，其中最引人注目的是一个明显的釉质发育不全（釉质变薄）。从CS小鼠模型的牙齿的组织学检查发现异常的门牙发育不全的釉质和紊乱的成釉细胞（釉质产生细胞）。CS小鼠模型中的成釉细胞似乎是过度增殖的，并显示极性丧失。我建议利用CS小鼠模型以及体外CS细胞模型，以确定激活的Ras信号对成釉细胞的影响。最终，我的目标是了解Ras在釉质形成（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，我们可以设计出更好的策略来预防，诊断和治疗蛀牙和其他釉质缺陷。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。 与公共卫生的关系：牙釉质是牙齿的坚硬外壳，可以保护牙齿免受腐蚀。牙釉质不能再生，目前标准的治疗方法是牙齿修复。通过了解釉质如何形成，我们可以设计改进的策略来预防，诊断和治疗蛀牙和其他釉质缺陷。

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.