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：
9262071
负责人：
Yuji MISHINA
金额：
$ 47.37万
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 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9262071
关键词：
Address Affect Anterior Apoptosis Biological Process Birth Blindness Bone Morphogenetic Proteins Cartilage Cell Death Cells Cephalic Chemicals Complex Congenital Abnormality Coupled Craniosynostosis Deformity Development Disease model Embryo Exhibits Fibroblast Growth Factor Forehead Gene Silencing Genes Genetic Genetic Counseling Goals Human Incidence Individual Joint structure of suture of skull Lead Live Birth Measures Mediating Mental Retardation Mesenchyme Methods Modeling Molecular Molecular Target Morphology Mus Mutation Neural Crest Newborn Infant Operative Surgical Procedures Pathogenesis Pathogenicity Pathway interactions Phenotype Polymers Population Prevalence Protocols documentation Series Shapes Signal Pathway Signal Transduction Signaling Protein Site Skeletal system Smad Proteins Social support Surgical sutures Syndrome System TP53 gene Therapeutic Time Tissues Up-Regulation WNT Signaling Pathway base cell fate specification craniofacial cranium deafness experimental study gain of function mutation genome wide association study human disease inhibitor/antagonist insight knock-down molecular targeted therapies mouse model mutant nanoscale novel overexpression premature premaxilla prevent public health relevance receptor binding skull abnormality stem cell population 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. Deafness, blindness, and mental retardation often accompany this finding and an extensive series of surgeries is commonly required. The estimated prevalence of craniosynostosis is 1:2,500 live births making it one of the most prevalent congenital malformations affecting the 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 show craniosynostosis is associated with mutations in several genes; however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling in craniosynostosis has been recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of the metopic suture via gain-of-function mutation in a BMP signaling component. This model is unique and important due to: 1) upregulation of p53- induced apoptosis is observed, 2) ectopic cartilage is formed at the site of fusion prior to premature fusion, and 3) the phenotype is rescued in the heterozygous null background of Bmpr1a indicating precise control of BMP signaling is critical for preventing craniosynostosis. Together these finding suggest novel mechanisms for premature suture fusion. We will identify critical downstream molecules and signaling pathways for craniosynostosis and establish treatment methods using chemical inhibitors for specific signaling pathways coupled with our newly developed gene silencing method. Our study will further define molecular pathways directly involved in the pathogenesis of premature fusion of cranial sutures leading to craniosynostosis and will provide better insights for potential molecular targets during therapeutic treatment of human cases.

描述（由适用提供）：颅骨突变是一种令人衰弱的疾病，其特征是过早的颅骨融合，导致颅骨形状异常。通常需要聋哑，失明和智力低下，涉及这一发现和一系列大量手术。颅突的估计患病率是1：2,500个活产，使其成为影响骨骼系统的最普遍的先天性畸形之一。拟议的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的分子机制。最近的研究表明，颅突式症与几种基因的突变有关。然而，颅突的大多数（70％）的遗传原因仍然未知。最近已经提出了BMP信号传导参与颅突中的。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信号成分中的功能增益突变对二元缝合线的过早融合。由于以下原因，该模型是独一无二的，而且很重要，因此观察到p53诱导的凋亡的上调，2）在融合过早融合之前的融合部位形成依托软骨，而3）3）表型在BMPR1A的杂合无效背景中拯救了BMP Signalsing的杂合无效背景，以预防BMP信号的精确控制。这些发现共同提出了过早缝合融合的新机制。我们将确定关键的下游分子和颅突的信号通路，并使用化学抑制剂与我们新开发的基因沉默方法相连的特定信号通路进行治疗方法。我们的研究将进一步定义直接参与颅骨突变融合发病机理的分子途径，并将为人类病例治疗期间的潜在分子靶标提供更好的见解。