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.
Neonatal hydrocephalus is a common developmental anomaly affecting the human nervous system with an estimated incidence of 1 to 3 per 1,000 live births1-4 creating an estimated healthcare burden of 2 billion dollars annually. The successful completion of this project will lead to insights into novel mechanisms involved in hydrocephalus, the understanding of which is important for identifying risk factors for this disorder. The results will potentially improve diagnosis, genetic risk assessment, and treatment of this important disorder.
|Zhang, Yan; Seo, Seongjin; Bhattarai, Sajag et al. (2014) BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet 23:40-51|