The Role of RAS/MAPK Signaling in Alveolar Process Development

描述（由申请人提供）：Ras蛋白是一个信号开关分子家族，主要通过激活丝裂原活化蛋白激酶（MAPK）级联来控制多种细胞反应，包括增殖、分化、存活和衰老。rasopathy是一组新定义的医学遗传综合征，是由Ras/MAPK通路的改变引起的。其中包括努南综合征、神经纤维瘤病、科斯特洛综合征和心-面-皮综合征。总而言之，Rasopathies是已知的最大的畸形综合征群之一，影响着bb10:1000的个体。使用它们作为模型为研究Ras信号在颅面和骨发育中的作用提供了独特的机会。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。与其他rasopathy一样，CS患者的阑尾骨骼经常受到影响。骨骼异常包括低骨量和身材矮小，导致Ras通路激活影响骨细胞功能的假设。然而，除了可能的破骨细胞过度活跃外，对Ras信号在骨稳态中的作用知之甚少。CS和其他ras病患者的颅面骨骼和牙列也受到严重影响，具有严重的功能和美容后果，但这些表型尚未得到系统的检查。拟议研究的总体目标是了解颅面骨发育如何受到种系Ras失调的影响，以及这种影响的具体作用机制。我们将集中在牙槽突，颌骨的一部分，包括牙槽。牙槽突独特的重塑能力为我们研究Ras信号在骨发育中的作用提供了一个很好的系统。特异性目的1将表征CS患者和小鼠模型的肺泡突表型。特异性Aim 2将确定Ras参与肺泡形成的细胞机制。最后，Specific Aim 3将确定Ras信号调控骨细胞功能的机制，并确定使用小分子治疗CS的可行性。为了实现这些目标，我们将检查患者的x线片，并通过形态学、组织学、细胞和分子技术分析各种小鼠遗传模型。该项目意义重大，因为更好地了解Ras信号干扰骨发育的机制将使我们能够开发新的和改进的策略，用于诊断和治疗CS，特别是RASopathies。

DESCRIPTION (provided by applicant): Ras proteins are a family of signal switch molecules that control multiple cellular responses, including proliferation, differentiation, survival and senescence, mostly through activation of the Mitogen-Activated Protein Kinase (MAPK) cascade. The RASopathies, a newly defined group of medical genetic syndromes, are caused by alterations of the Ras/MAPK pathway. These include, among others, Noonan syndrome, neurofibromatosis 1, Costello syndrome (CS) and cardio-facio-cutaneous syndrome. Taken together, the Rasopathies are one of the largest groups of malformation syndromes known, affecting >1:1000 individuals. Using them as a model provides a unique opportunity to study the role of Ras signaling in craniofacial and bone development. CS is caused by a heterozygous de novo germline mutation in HRAS that results in a constitutively active Ras protein. As in other RASopathies, the appendicular skeleton of CS patients is frequently affected. Skeletal anomalies include low bone mass and short stature, leading to the hypothesis that activation of the Ras pathway affects bone cell function. However, apart from possible osteoclast hyperactivity, little is known about the role of Ras signaling in bone homeostasis. The craniofacial skeleton and the dentition of patients with CS and other RASopathies are also significantly affected, with severe functional and cosmetic consequences, but these phenotypes have yet to be systematically examined. The overall goal of the proposed research is to understand how craniofacial bone development is affected by germline Ras dysregulation, as well as the specific mechanisms of action underlying this effect. We will focus on the alveolar process, the part of the jawbone that contains the tooth sockets. The unique ability of the alveolar process to remodel provides us with an excellent system for studying Ras signaling function in bone development. Specific Aim 1 will characterize the alveolar process phenotype in CS patients and mouse model. Specific Aim 2 will determine the cellular mechanisms that underlie Ras involvement in alveolar process formation. Finally, Specific Aim 3 will determine the mechanism by which Ras signaling regulates bone cell function, and also determine the feasibility of using small molecules to treat CS. To accomplish these goals we will examine patients' radiographs and analyze various mouse genetic models by morphological, histological, cellular, and molecular techniques. This project is significant because a better understanding of the mechanism by which Ras signaling disrupts bone development will enable us to move towards developing new and improved strategies for diagnosis and treatment of CS in particular and RASopathies in general.