Role of Neural Progenitor Cells in the Development of Neonatal Hydrocephalus

神经祖细胞在新生儿脑积水发展中的作用

• 批准号: 8657125
• 负责人: Val C. Sheffield
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657125
• 关键词: Affect; Bardet-Biedl Syndrome; Cells; Cerebral Ventricles; Cilia; Communities; Data; Defect; Development; Diagnosis; Disease; Etiology; Functional disorder; Genetic; Genetic Variation; Goals; Healthcare; Human; Hydrocephalus; Incidence; Lead; Life; Live Birth; Mechanics; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Mutant Strains Mice; Nature; Neonatal; Nervous system structure; Neurons; Obstruction; PDGFRB gene; Pathogenesis; Pathway interactions; Pharmacologic Substance; Phenotype; Play; Research; Risk Factors; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Therapeutic; base; cell type; ciliopathy; genetic risk assessment; improved; insight; mortality; mouse model; mutant mouse model; nerve stem cell; notch protein; novel; public health relevance

DESCRIPTION (provided by applicant): Neonatal hydrocephalus is a common developmental anomaly affecting the human nervous system with an estimated incidence of 1 to 3 per 1,000 live births creating an estimated healthcare burden of 2 billion dollars annually. Hydrocephalus leads to the expansion of cerebral ventricles and is associated with significant morbidity and mortality with mortality rates as high as 35%. A significant portion of neonatal hydrocephalus is idiopathic in nature. The major goal of this proposal is the identification of molecular mechanisms underlying hydrocephalus for the purpose of developing novel medical treatments. This goal will be pursued by utilizing mouse models of human ciliopathies. Ciliopathies are a group of disorders that display overlapping phenotypes with a common etiology of cilia defects. Ciliopathy models have described that develop hydrocephalus as a result of altered ependymal cilia beat mechanics resulting in abnormal flow of CSF. In this proposal, we challenge the notion that motile cilia defects are the sole cause of hydrocephalus in ciliopathy models with our central hypothesis that abnormal development of specific neural progenitor cells during early development plays a major role in hydrocephalus. The central hypothesis and the specific aims of this proposal are based on strong preliminary data. In specific aim 1, we will build upon strong preliminary data that show that abnormal development of specific neural progenitor cells lead to hydrocephalus in a specific mouse model of the human disorder, Bardet-Biedl Syndrome (BBS). We will determine the specific neuroprogenitor cells involved in hydrocephalus, and determine the defective signaling pathways in the neuroprogenitor cells that contribute to hydrocephalus. In specific aim 2, we will determine whether similar mechanisms apply to other ciliopathy mouse models. In specific aim 3, we will investigate the potential for modifying the hydrocephalic phenotype in ciliopathy mouse models utilizing pharmaceuticals and genetic methods to manipulate signaling pathways identified in Aim 1 and Aim 2. Successful completion of the research outlined in this application will advance the understanding of cilia dysfunction and cilia related diseases in general, especially the molecular mechanism underlying the pathogenesis of hydrocephalus. The results of this study will have significant implications for therapeutic treatment of neonatal hydrocephalus.

描述（由申请人提供）：新生儿脑积水是一种常见的发育异常，影响人类神经系统，估计每1000只活产1至3个活产率每年造成估计的医疗保健负担为20亿美元。脑积水会导致脑室的扩张，并与死亡率的显着发病率和死亡率相关，死亡率高达35％。新生儿脑积水的很大一部分本质上是特发性的。该提案的主要目的是确定脑积水基于的分子机制，目的是开发新的医疗治疗。通过利用人类纤毛病的小鼠模型来实现此目标。纤毛病是一组疾病，它们表现出具有纤毛缺陷常见病因的重叠表型。纤毛病模型描述的是，由于cSf异常流动的脑膜cil骨peat机械的改变，发展脑积水。在此提案中，我们挑战了纤毛缺陷是与我们中央的纤毛病模型中脑积水的唯一原因 假设早期发育过程中特定神经祖细胞异常发育在脑积水中起主要作用。该提案的中心假设和具体目标是基于强大的初步数据。在特定目标1中，我们将建立强大 初步数据表明，在人类疾病的特定小鼠Bardet-Biedl综合征（BBS）的特定小鼠模型中，特定神经祖细胞的异常发育导致脑积水。我们将确定参与脑积水的特定神经元素细胞，并确定有助于脑积水的神经元基因细胞中的有缺陷的信号传导途径。在特定的目标2中，我们将确定是否适用于其他纤毛病小鼠模型。在特定目标3中，我们将研究使用药物和遗传方法来操纵AIM 1和AIM 2的纤毛病小鼠模型中修改脑脑表型的潜力。成功完成了该应用程序中概述的研究将推动对纤毛功能障碍和Cilia功能障碍的理解。 一般而言，相关疾病，尤其是脑积水发病机理的基本机制。这项研究的结果将对新生儿脑积水的治疗治疗产生重大影响。