Role of Neural Progenitor Cells in the Development of Neonatal Hydrocephalus

描述（由申请方提供）：新生儿脑积水是一种影响人类神经系统的常见发育异常，估计发病率为1 - 3/1000例活产，每年造成的医疗负担估计为20亿美元。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。该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变的小鼠模型来实现。纤毛病是一组表现出重叠表型的疾病，其共同病因是纤毛缺陷。纤毛病模型已经描述了由于室管膜纤毛搏动机制改变导致CSF的异常流动而发展脑积水。在这个提议中，我们挑战了这样一种观点，即运动纤毛缺陷是纤毛病变模型中脑积水的唯一原因， 早期发育过程中特定神经前体细胞的异常发育在脑积水中起主要作用的假说。这项建议的核心假设和具体目标是以强有力的初步数据为基础的。在具体目标1中，我们将建立在强大的 初步数据显示，在人类疾病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前体细胞，并确定导致脑积水的神经前体细胞中有缺陷的信号通路。在具体目标2中，我们将确定类似的机制是否适用于其他纤毛病小鼠模型。在具体目标3中，我们将研究利用药物和遗传学方法来操纵目标1和目标2中鉴定的信号传导途径，从而改变纤毛病小鼠模型中脑积水表型的潜力。成功完成本申请中概述的研究将促进对纤毛功能障碍和纤毛 相关疾病，特别是脑积水发病机制的分子机制。本研究的结果将对新生儿脑积水的治疗具有重要意义。

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.