The Role of RAS/MAPK Signaling in Alveolar Process Development

RAS/MAPK 信号传导在肺泡过程发育中的作用

• 批准号: 8732467
• 负责人: Amnon Sharir
• 金额: $ 5.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732467
• 关键词: Affect; Alveolar Process; Bone Development; Bone Resorption; Cell physiology; Cosmetics; Costello syndrome; Cutaneous; Defect; Dentition; Deposition; Development; Diagnosis; Dyes; Family; Fluorochrome; Genetic; Genetic Models; Germ-Line Mutation; Goals; HRAS gene; Head; Histology; Homeostasis; Human; Hyperactive behavior; In Vitro; Individual; Lead; Lytic; MEKs; Mandible; Measures; Medical Genetics; Minerals; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphogenesis; Mus; Neurofibromatosis 1; Noonan Syndrome; Osteoblasts; Osteoclasts; Osteogenesis; Pathway interactions; Patients; Phenotype; Process; Research; Role; Scanning; Signal Transduction; Skeleton; Specific qualifier value; Syndrome; System; Techniques; Tissues; Tooth Socket; X-Ray Computed Tomography; alveolar bone; bone; bone cell; bone mass; craniofacial; improved; in vivo; inhibitor/antagonist; long bone; malformation; mouse model; novel; public health relevance; ras Proteins; research study; response; senescence; skeletal; small molecule; treatment strategy

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.

描述（由申请人提供）：Ras蛋白是一个信号开关分子家族，主要通过激活促分裂原活化蛋白激酶（MAPK）级联来控制多种细胞反应，包括增殖、分化、存活和衰老。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。其中包括努南综合征、1型神经纤维瘤病、科斯特洛综合征（CS）和心-面-皮肤综合征。总的来说，Rasopathies是已知的最大的畸形综合征组之一，影响>1：1000的个体。使用它们作为模型提供了一个独特的机会来研究Ras信号在颅面和骨骼发育中的作用。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。与其他RASopathies一样，CS患者的apapproxial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跃外，对Ras信号在骨稳态中的作用知之甚少。CS和其他RASopathies患者的颅面骨骼和牙列也受到显着影响，具有严重的功能和美容后果，但这些表型尚未进行系统检查。拟议研究的总体目标是了解颅面骨发育如何受到生殖细胞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，包含牙槽。牙槽突的独特能力，重塑为我们提供了一个很好的系统，研究Ras信号在骨发育中的功能。具体目标1将表征CS患者和小鼠模型中的肺泡突表型。具体目标2将确定的细胞机制，Ras参与肺泡过程的形成。最后，具体目标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、细胞和分子技术分析各种小鼠遗传模型。这个项目是重要的，因为更好地了解Ras信号传导破坏骨发育的机制将使我们能够朝着开发新的和改进的战略，特别是CS和RASopathies的诊断和治疗。