Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

BMP信号增强导致颅缝早闭的分子发病机制

基本信息

批准号：
8510106
负责人：
Yuji MISHINA
金额：
$ 10.42万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8510106
关键词：
Alleles Anterior Biological Process Birth Blindness Bone Morphogenetic Proteins Cartilage Cells Cephalic Chemicals Complex Congenital Abnormality Craniosynostosis Critical Pathways Development Disease model Dura Mater Event Exhibits Fibroblast Growth Factor Forehead Genetic Genetic Counseling Goals Human Incidence Individual Joint structure of suture of skull Lead Live Birth MAPK3 gene Measures Mediating Mental Retardation Mesenchyme Methods Modeling Molecular Molecular Target Mus Mutation Neural Crest Newborn Infant Operative Surgical Procedures Pathogenesis Pathway interactions Phenotype Phosphorylation Prevalence Protocols documentation Shapes Signal Pathway Signal Transduction Signaling Molecule Site Skeletal system Social support Surgical sutures Therapeutic Tissues Up-Regulation bone craniofacial cranium gain of function mutation inhibitor/antagonist insight mouse model mutant novel overexpression premature prevent public health relevance receptor receptor binding research study suture fusion

项目摘要

DESCRIPTION (provided by applicant): Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion, resulting in abnormal skull shape, blindness and mental retardation. The prevalence of craniosynostosis is at 1 in 2,500 live births, which is one of the highest incidences of congenital malformation of skeletal system. The long-term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies demonstrated that craniosynostosis is associated with mutations in FGF signaling components, Twist, Msx2 and Efnb1, however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of-function mutation in a BMP signaling component. This model is unique and important because 1) upregulation of FGF signaling is observed, 2) ectopic cartilage is formed at the site of fusion prior to the fusion, and 3) the phenotype is rescued in heterozygous null background of BMPRIA, indicating that the precise control of BMP signaling is critical to prevent craniosynostosis. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases. PUBLIC HEALTH RELEVANCE: In this proposal, we will define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of- function mutation in a BMP signaling component. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.

描述（由申请人提供）：颅缝早闭是一种使人衰弱的疾病，其特征是颅缝过早融合，导致颅骨形状异常、失明和智力低下。颅缝早闭的患病率为每 2,500 名活产儿中就有 1 人患有颅缝早闭，是发病率最高的骨骼系统先天畸形之一。拟议研究的长期目标是确定 BMP 信号成分功能获得性突变导致颅缝早闭的分子机制。最近的研究表明，颅缝早闭与 FGF 信号成分 Twist、Msx2 和 Efnb1 的突变有关，然而，大多数（70%）颅缝早闭的遗传原因仍不清楚。最近提出 BMP 信号参与颅缝早闭。我们开发了一种新的颅缝早闭小鼠模型，其特征是 BMP 信号成分中的功能获得性突变导致同位缝过早融合。该模型是独特且重要的，因为 1) 观察到 FGF 信号传导的上调，2) 融合前在融合位点形成异位软骨，3) 在 BMPRIA 杂合零背景中挽救了表型，表明精确的控制 BMP 信号传导对于预防颅缝早闭至关重要。我们将使用该模型来研究导致发病机制的分子机制。我们的研究将进一步明确直接参与颅缝过早融合导致颅缝早闭发病机制的分子途径，因此将为人类病例治疗的潜在分子靶点提供更好的见解。公共健康相关性：在本提案中，我们将定义 BMP 信号成分中的功能获得性突变导致颅缝早闭的分子机制。大多数（70%）颅缝早闭的遗传原因仍不清楚。最近提出 BMP 信号传导参与颅缝早闭。我们开发了一种新的颅缝早闭小鼠模型，其特征是 BMP 信号成分中的功能获得性突变导致同位缝过早融合。我们将使用该模型来研究导致发病机制的分子机制。我们的研究将进一步明确直接参与颅缝过早融合导致颅缝早闭发病机制的分子途径，因此将为人类病例治疗的潜在分子靶点提供更好的见解。