Role of Neural Progenitor Cells in the Development of Neonatal Hydrocephalus

描述（由申请人提供）：新生儿脑积水是一种常见的影响人类神经系统的发育异常，估计每1000名活产婴儿中有1至3例的发病率，估计每年造成20亿美元的医疗负担。脑积水导致脑室扩张，并与显著的发病率和死亡率相关，死亡率高达35%。很大一部分新生儿脑积水是特发性的。本提案的主要目标是确定脑积水的分子机制，以开发新的医学治疗方法。这一目标将通过利用人类纤毛病的小鼠模型来实现。纤毛病是一组疾病，显示重叠表型与纤毛缺陷的共同病因。纤毛病模型描述了由于室管膜纤毛搏动力学改变导致脑脊液异常流动而发生脑积水。在这一建议中，我们挑战的概念，即运动性纤毛缺陷是脑积水的唯一原因在纤毛病模型与我们的中心

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.