Congenital brain malformations caused by aberrant head mesenchymal signaling

头部间质信号异常引起的先天性脑畸形

• 批准号: 8539859
• 负责人: Kathleen Joyce Millen
• 金额: $ 44.24万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539859
• 关键词: Affect; Biological Assay; Biology; Brain; Breeding; Candidate Disease Gene; Cerebellar malformation; Cerebellum; Clinical; Congenital Abnormality; Custom; Dandy-Walker Syndrome; Defect; Development; Developmental Gene; Diagnosis; Diagnostic; Disease; Electroporation; Embryo; Family; Future; Gene Transfer Techniques; Genes; Genetic Heterogeneity; Goals; Growth Factor; Head; Human; Hydrocephalus; In Vitro; Informatics; Lasers; Lead; Lip structure; Live Birth; Meningeal; Meninges; Mesenchymal; Mesenchyme; Methods; Molecular; Molecular Biology; Motor; Mus; Neurodevelopmental Disorder; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phenotype; Posterior Fossa; RNA Interference; Regulation; Role; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; System; Testing; Transgenic Mice; Ventricular; Walkers; base; brain malformation; brain pathway; clinical phenotype; cohort; computerized data processing; design; developmental genetics; gene discovery; gene interaction; genome-wide; improved; in vivo; innovation; interdisciplinary approach; malformation; mouse model; mutant; neurodevelopment; novel; prognostic; programs; research study; tool; transcription factor

DESCRIPTION (provided by applicant): This application describes an interdisciplinary approach involving basic and clinical scientists employing new and innovative informatic, genetic and developmental strategies to identify the underlying pathogenesis and causative genes for Dandy-Walker malformation, the most common structural malformation of the cerebellum. Dandy-Walker malformation is common, affecting 1/3000 live births and causes significant motor and intellectual delay and yet is poorly understood. Our group has identified the only 2 characterized loci for this clinically and genetically heterogeneous birth defect. Our analysis of mouse models has lead us to the hypothesis that disruption of mesenchymal signaling to the developing cerebellum is critical to the developmental pathogenesis of this birth defect. The recognition that the meninges is a critical regulator of CNS development is a recent paradigm shift in the field of neurodevelopment and the basic biology and molecular pathways of these interactions is not known. Further, it has become apparent that disrupted meningeal signaling underlies not only the significant clinical phenotypes of posterior fossa disorders such as Dandy-Walker, but has broad implications for the pathogenesis of large group of neurodevelopmental disorders that also involve meningeal signaling including ACC and others. The experiments outlined in this proposal are designed to identify pathways and mechanisms for posterior fossa mesenchymal regulation of cerebellar development, using Foxc1, the most recently identified Dandy-Walker gene, as an entry point. Aims 1-3 use novel in vitro and in vivo assays including explant culture, electroporation, RNAi and BAC transgenesis together with extensive informatic analyses to identify and validate the signaling pathways from the posterior fossa to the adjacent developing cerebellum which modulate Dandy-Walker related phenotypes in mouse models. In Aim 4 we will then sequence the best Dandy-Walker candidates from the first 3 Aims, in a cohort of human Dandy-Walker patients to identify new disease-causative genes. Together these synergistic mouse and human experiments will define new biology regarding mesenchymal control of neural development and identify new DWM genes, which will immediately improve diagnosis for affected families and will be essential for future prognostic studies.

描述（由申请人提供）：本申请描述了一种跨学科方法，涉及基础和临床科学家，采用新的和创新的信息学、遗传和发育策略来确定 Dandy-Walker 畸形（最常见的小脑结构畸形）的潜在发病机制和致病基因。 Dandy-Walker 畸形很常见，影响 1/3000 的活产，并导致严重的运动和智力迟缓，但人们对此知之甚少。我们的小组已经确定了这种临床和遗传异质性出生缺陷的唯一 2 个特征位点。我们对小鼠模型的分析使我们得出这样的假设：发育中小脑的间充质信号传导的破坏对于这种出生缺陷的发育发病机制至关重要。脑膜是中枢神经系统发育的关键调节因子的认识是神经发育领域最近的范式转变，而这些相互作用的基本生物学和分子途径尚不清楚。此外，很明显，脑膜信号传导中断不仅是后颅窝疾病（例如 Dandy-Walker）的重要临床表型的基础，而且对大量也涉及脑膜信号传导（包括 ACC 等）的神经发育障碍的发病机制具有广泛的影响。本提案中概述的实验旨在利用最近发现的 Dandy-Walker 基因 Foxc1 作为切入点，确定后颅窝间充质调节小脑发育的途径和机制。目标 1-3 使用新颖的体外和体内测定方法，包括外植体培养、电穿孔、RNAi 和 BAC 转基因，以及广泛的信息学分析，以识别和验证从后颅窝到相邻发育中小脑的信号通路，这些信号通路在小鼠模型中调节 Dandy-Walker 相关表型。在目标 4 中，我们将对人类 Dandy-Walker 患者队列中前 3 个目标中最好的 Dandy-Walker 候选者进行测序，以识别新的致病基因。这些协同的小鼠和人体实验将定义有关神经发育的间充质控制的新生物学，并鉴定新的 DWM 基因，这将立即改善受影响家庭的诊断，并对未来的预后研究至关重要。