Our research focuses on molecular mechanisms that govern mammalian brain development, such as neurogenesis, neuronal migration, differentiation and synaptic connectivity. Abnormalities in these processes underlie cognitive dysfunction in developmental brain disorders and in the aging or injured brain. Our short-term goal is to improve our mechanistic understanding of these diseases through experimental approaches that exploit genetically modified mouse models and human induced pluripotent stem cells (iPSC). The long-term goal of this work is to foster the development of new strategies for the treatment of neurological disorders and traumatic brain injury. Current projects include:
1. The function of Reelin in brain development. Reelin is an extracellular protein that controls neuronal migration during embryonic brain development, and promotes dendrite outgrowth and synapse formation during postnatal development and in the adult brain. Loss of REELIN function in humans cause a severe neurological disorder called lissencephaly with cerebellar hypoplasia, and mutations or polymorphisms in this gene are associated with cognitive dysfunctions such as schizophrenia and autism. Using the Reelin mutant mouse reeler and conditional knock out mutants that are defective in Reelin signal transduction, we are currently investigating the cellular and molecular mechanisms of Reelin activity during brain development.
2. The Akt/mTOR signaling pathway in traumatic brain injury. Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, and novel pharmacological treatments are urgently needed to limit cognitive dysfunction and improve recovery. We are currently investigating the role of a major signal transduction pathway, including the Akt and mTOR kinases, in neuronal death and brain inflammation after TBI. Using both in vivo mouse models and in vitro neuronal culture models of TBI, as well as pharmacological inhibitors of the Akt/mTOR pathway we study whether manipulations of this signaling activity can be used to improve functional recovery after injury. This project is currently supported by the New Jersey Commission on Brain Injury Research.
3. Identification of cellular phenotypes of Tuberous Sclerosis Complex using patient-derived iPSCs. Tuberous Sclerosis Complex (TSC) is a developmental disorder characterized by tumor susceptibility in multiple organs, brain malformations, and neurological manifestations including epilepsy and autism. Despite considerable progress in understanding the genetic and signaling mechanisms underlying the disease, effective treatments are still lacking, particularly with regard to the control of neurological symptoms. We are currently developing induced pluripotent stem cell (iPSC) lines from TSC patient and unaffected siblings, and deriving neuronal progenitor cell (NPC) lines. These cells are then used to obtain neuronal cultures and to investigate cellular and molecular phenotypes of the disease. This work will help elucidate the mechanism of disease in TSC, and facilitate the identification of drugs that can restore normal neural function, advancing treatment and improving the lives of the patients. This project is currently supported by the National Institute of Health and by the Tuberous Sclerosis Alliance.