Aim 1: Understand how a circuit is formed from neural stem cells to synaptic integration in health and in developmental mTORopathies
Our past work on neural stem cells and postnatal neurogenesis has created a platform of knowledge that has helped us better understand what goes wrong when a gene is mutated like in the case of TSC. By using TSC mice and in vivo strategies to manipulate gene expression in neural stem cells, we have recapitulated TSC lesions including cortical malformations (called tubers), white matter heterotopia, non-malignant astrocytoma, and migratory heterotopia in different brain structures. In addition, we found that mTOR-hyperactive neurons form abnormal network through abnormal dendritic patterning and placement. We are also uncovering the molecular pathway that allows neural stem cells to remain in a quiescent/dormant state. We are harvesting these mechanisms to selectively reactivate dormant neural stem cells for de novo generation of adult born neurons. This strategy has significant implications for brain repair following an injury or neurodegenerative diseases.
Aim 2: Prevent lesion formations and associated neurological symptoms in TSC and similar developmental mTORopathies
We are using various cellular approaches to identify the mTOR-dependent players responsible for brain malformations. Commercially available drugs will be tested to examine prevention of lesion formation during in utero and neonatal life.
Aim 3: Understand the molecular basis of cognitive dysfunctions in TSC
We propose a conserved molecular convergence onto specific intracellular molecules across cognitive disorders associated with dysregulated mTOR signaling. Normalizing the functions of these specific molecules in mTORopathies may provide a novel therapeutic avenue to improve cognitive function. Using TSC mice and an array of cellular approaches (including proteomics from synapses), we have identified synaptic proteins involved in plasticity, the cellular substrate of memory, that are dysregulated in TSC. We are dissecting the players downstream of mTOR that are responsible for such dysregulation.