SINGLE SUTURE CRANIOSYNOSTOSIS: CANDIDATE GENE AND PATHWAY DISCOVERY

单缝颅缝早闭：候选基因和通路的发现

基本信息

批准号：
7595083
负责人：
MICHAEL L CUNNINGHAM
金额：
$ 57.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-25 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7595083
关键词：
Address Affect Calvaria Candidate Disease Gene Code Complex Congenital abnormal Synostosis Counseling Craniosynostosis DNA Resequencing Data Development Developmental Gene Diagnosis FGFR1 gene FGFR2 gene FGFR3 gene Face Family Fibroblast Growth Factor Receptors Frequencies Functional RNA Future Gene Expression Genes Genetic Genomics Growth Human International Intracranial Hypertension Investigation Joint structure of suture of skull Knowledge Laboratories Large-Scale Sequencing Live Birth Measures Microarray Analysis Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Neurocognitive Osteoblasts Pathogenesis Pathologic Pathway interactions Patients Pattern Play Positioning Attribute Promoter Regions Reconstructive Surgical Procedures Regulation Research Role Series Shapes Surgical Management Surgical sutures Syndrome TWIST1 gene Variant Work base case control cranium design developmental genetics fetal gene discovery genetic variant genome wide association study interdisciplinary approach malformation mortality novel rapid growth research study success text searching

项目摘要

DESCRIPTION (provided by applicant): Craniosynostosis is the pathologic fusion of the calvaria. Over the past ten years significant advances have been made in our understanding of multiple malformation syndromes that involve craniosynostosis. It has been shown that mutations in the fibroblast growth factor receptors (FGFR1-3), TWIST1, MSX2, and the EFNB1 each cause craniosynostosis syndrome in humans. This extensive body of work, carried out in several international laboratories, has significantly impacted how we diagnose and counsel families with syndromic craniosynostosis. Despite the rapid growth of knowledge regarding syndromic forms, the causes of isolated synostosis remain elusive. Though vastly more common than syndromic forms, relatively little research has focused on the molecular pathogenesis of isolated craniosynostosis. The frequency of this group of calvarial malformations, the need for complex surgical management and its associated morbidity make isolated craniosynostosis a candidate for intense scientific investigation. We propose the use of three approaches to identify and characterize candidate genetic causes of isolated craniosynostosis: high throughput genomic sequencing, large-scale microarray expression analysis, and developmental gene expression. We have used knowledge gained from the investigation of normal calvarial development and syndromic forms of craniosynostosis to develop two interrelated hypotheses: (A) Rare sequence variants in two classes of genes result in isolated craniosynostosis: those that regulate suture development and those that, when mutated, cause syndromic craniosynostosis; and (B) Genetic pathways involved in cranial suture development and those impacted in the syndromic craniosynostoses are similarly affected in isolated, non-syndromic craniosynostosis. In this proposal, we describe a series of experiments designed to discover potential molecular causes of isolated craniosynostosis through the identification of rare genetic variants, altered calvarial osteoblast gene expression, and the temporal and spatial expression of candidate genes. The expertise of our research team and the availability of complementary high throughput approaches has allowed for the development of a comprehensive investigation of the genetic and developmental pathogenesis of isolated craniosynostosis.

描述（由申请人提供）：颅突式症是瓦尔瓦里亚的病理融合。在过去的十年中，我们了解涉及颅突的多种畸形综合征的理解，取得了重大进展。已经表明，成纤维细胞生长因子受体（FGFR1-3），Twist1，MSX2和EFNB1中的突变每个引起人类的颅骨突出综合征。在几个国际实验室进行的这项广泛的工作，对我们诊断和咨询综合症颅脑动脉漏洞的家庭的咨询方式极大地影响了。尽管关于综合征形式的知识迅速增长，但孤立的阴影的原因仍然难以捉摸。尽管比综合征形式更为普遍，但相对较少的研究集中在分离的颅突发作的分子发病机理上。这一组钙调畸形的频率，对复杂的手术管理的需求及其相关的发病率使孤立的颅骨突变病成为强烈的科学研究的候选者。我们提出了使用三种方法来识别和表征分离出颅突的候选遗传原因：高吞吐量基因组测序，大规模的微阵列表达分析和发育基因表达。我们使用了从对正常钙颅发育和综合征形式的颅突变形式的研究中获得的知识来发展两个相互关联的假设：（a）两类基因中的罕见序列变异会导致孤立的颅脑流失：那些调节缝隙发育的人，以及那些在突变时进行了突变的促颅的发展。，导致综合征颅突变；（b）与颅缝合发育有关的遗传途径以及综合征颅颅突出的途径在孤立的非综合颅骨突变症中类似地影响。在该提案中，我们描述了一系列实验，旨在通过鉴定稀有遗传变异，改变钙质成骨细胞基因的表达以及候选基因的时间和空间表达来发现分离的颅骨造for的潜在分子原因。我们的研究团队的专业知识以及互补的高通量方法的可用性允许对孤立的颅突变症的遗传和发育发病机理进行全面研究。