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

基本信息

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
项目类别：
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

项目摘要

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，涉及基本和临床科学家，采用了新的和创新的信息，遗传和发育策略来识别dandy walker畸形的潜在发病机理和致病基因，这是小脑脑中最常见的结构畸形。 Dandy-Walker畸形很常见，影响了1/3000个活产，并引起大量的运动和智力延迟，但知识渊博。我们的小组已经确定了该临床和遗传异质性先天缺陷的仅有的两个基因座。我们对小鼠模型的分析使我们提出了一个假设，即间质信号传导对发育中的小脑的破坏对于这种先天缺陷的发育发病机理至关重要。认识到脑膜是中枢神经系统发育的关键调节剂的认识是神经发育领域的范式转变，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，破坏的脑膜信号传导不仅是后孔障碍症（如dandy-walker）的重要临床表型的基础，而且对大量神经发育疾病的发病机理具有广泛的意义，这些发病机理也涉及包括ACC在内的脑膜信号和其他人在内。该提案中概述的实验旨在识别小脑发育后窝间充质调控的途径和机制，使用FOXC1（最近确定的dandy-Walker基因）作为入口点。 AIMS 1-3使用新型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分析，以识别和验证从后窝到相邻开发大脑的信号传导途径，从而调节小鼠模型中的dandy-walker相关的现象。在AIM 4中，我们将在人类的丹迪步行者患者队列中对前三个目标的最佳dandy-Walker候选者进行序列，以鉴定新的可疾病造成的基因。这些协同的小鼠和人类实验将共同定义有关神经发育的间充质控制的新生物学，并确定新的DWM基因，这将立即改善受影响家庭的诊断，对于未来的预后研究至关重要。