The Role of RAS/MAPK Signaling in Alveolar Process Development

描述(申请人提供)：RAS蛋白是一个信号开关分子家族，控制多种细胞反应，包括增殖、分化、生存和衰老，主要通过激活丝裂原激活蛋白激酶(MAPK)级联来实现。Rasopathies是一组新定义的医学遗传综合征，由RAS/MAPK通路的改变引起。这些疾病包括努南综合征、神经纤维瘤病1、科斯特罗综合征(CS)和心面部皮肤综合征。综上所述，Rasopathies是已知的最大的畸形综合征组之一，影响1：1000人。利用它们作为模型，为研究RAS信号在颅面和骨骼发育中的作用提供了一个独特的机会。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。与其他类风湿疾病一样，CS患者的附件骨骼经常受到影响。骨骼异常包括骨量低和身材矮小，这导致了RAS通路的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动外，对RAS信号在骨稳态中的作用知之甚少。CS和其他类风湿疾病患者的头面部骨骼和牙列也受到显著影响，具有严重的功能和美容后果，但这些表型尚未得到系统检查。这项拟议研究的总体目标是了解种系RAS失调如何影响头面部骨骼发育，以及这种影响背后的具体作用机制。我们将重点介绍牙槽突，即颌骨中包含牙槽的那部分。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。具体目标1将描述CS患者和小鼠模型的肺泡突表型。具体目标2将确定RAS参与肺泡突起形成的细胞机制。最后，特异靶3将确定RAS信号调节骨细胞功能的机制，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光片，并通过形态学、组织学、细胞学和分子技术分析各种小鼠遗传模型。这个项目意义重大，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，特别是CS和Rasopathies的诊断和治疗。

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.