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：
8230522
负责人：
Yuji MISHINA
金额：
$ 38.24万
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/8230522
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）：颅突式症是一种令人衰弱的疾病，其特征是过早的颅骨缝合融合，导致颅骨形状异常，失明和智力低下。颅突的患病率为2500例活产，这是骨骼系统先天性畸形的最高发生率之一。拟议研究的长期目标是定义BMP信号传导成分中功能增益突变导致颅突式症的分子机制。最近的研究表明，颅突式症与FGF信号传导成分中的突变有关，Twist，MSX2和EFNB1，但是，大多数颅面性脑流osisosisosis的遗传原因（70％）仍然未知。最近提出了BMP信号传导与颅突的涉及。我们开发了一种新的小鼠模型，用于颅突的变性，其特征在于通过在BMP信号传导成分中通过功能障碍突变对Metopic缝合线的过早融合。该模型是独特而重要的，因为1）观察到FGF信号传导的上调，2）在融合之前的融合部位形成了异位软骨，而3）3）表型在BMPRIA的无效背景中挽救了表型，表明BMP信号的精确控制对预防颅骨症至关重要。我们将使用该模型研究导致发病机理的分子机制。我们的研究将进一步定义分子途径直接涉及导致颅突的颅缝线过早融合的发病机理，因此将为潜在的分子靶标提供更好的见解，以治疗人类病例的治疗。公共卫生相关性：在此提案中，我们将定义BMP信号传导成分中功能增益突变导致颅面性突变的分子机制。大多数（70％）颅突变的遗传原因尚不清楚。最近提出了BMP信号传导与颅突的涉及。我们开发了一种新的小鼠模型，用于颅突的变性，其特征是通过BMP信号分量中的功能增益突变对Metopic缝合线的过早融合。我们将使用该模型研究导致发病机理的分子机制。我们的研究将进一步定义分子途径直接涉及导致颅突的颅缝线过早融合的发病机理，因此将为潜在的分子靶标提供更好的见解，以治疗人类病例的治疗。