Research Projects

Developmental hydrocephalus is among the most common neurodevelopmental disorders in children, with often devastating outcomes. About 12,000 pediatric cases of developmental hydrocephalus are reported every year in India. New therapeutic approaches are urgently needed since current treatment requires invasive surgeries with associated medical complications. Hydrocephalus is characterized by abnormal expansion of brain ventricles and progressive accumulation of cerebrospinal fluid. Misregulation of PI3K-AKT-MTOR and RAS-RAF-ERK signaling pathways has been identified to be instrumental in causing hydrocephalus and a wide spectrum of neurodevelopmental disorders, including brain malformations, intractable epilepsy, intellectual delay, and autism. Mutations in Neurofibromin 1 (NF1), a critical negative regulator of both PI3K-AKT-MTOR and RAS-RAF-ERK pathways, are implicated in causing the same spectrum of brain disorders in humans. However, how NF1 loss results in the initiation and progression of hydrocephalus remains elusive. Here, we aim to study the Nf1 expression profile in developing wildtype mouse brains to get a better understanding of its spatiotemporal expanse and cellular localization during brain development. Parallelly, we will investigate the mechanisms underlying Nf1-related developmental hydrocephalus and associated anomalies, using a brain-specific conditional mouse model of early-onset loss of Nf1, available in our lab. In addition to histological and histochemical analyses, we will specifically compare the development and functionality of ependymal cells between control and mutant brains, using high-resolution microscopy, electron microscopy, and live imaging. We will also identify possible alterations in signaling pathways due to Nf1 loss. These studies, together, will provide important insights into developmental, cellular, and molecular processes regulated by Nf1. Finally, we will introduce commercially available small-molecule pathway regulators in our mutant mice to preclinically rescue or attenuate the severity of the hydrocephalus phenotype. Overall, our proposed project will unravel the fundamental underpinnings of developmental hydrocephalus and can suggest potential therapeutic targets for the treatment of developmental hydrocephalus.

Hydrocephalus, Mouse model, Neurofibromin 1, Neurodevelopmental disorders, Therapeutic targets