Biology of glutamate transporters; Molecular mechanisms of neurological diseases including Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and epilepsy; Drug discovery and development for CNS disorders.
Excitatory amino acid transporter 2 (EAAT2) is primarily localized in peri-synaptic processes of astrocytes closely associated with excitatory synaptic contacts and is responsible for 80-90% of all glutamate transport in the CNS. EAAT2 plays a critical role in the homeostatic regulation of extracellular glutamate levels to prevent excess glutamate-mediated neurotoxicity. EAAT2 also plays an essential role in cognitive functions. EAAT2 has been implicated in the pathogenesis of many neurological diseases, such as Alzheimer’s disease and ALS. Several lines of evidence indicate that up-regulation of EAAT2 protein provides significant beneficial effects in many animal models of disease and is a potential therapeutic strategy. Expression of EAAT2 protein is highly regulated at the translational level. This translational regulation mechanism plays a critical role in regulation of glutamate uptake function and synaptic activity. We previously executed high-throughput screening to search for compounds that increase EAAT2 translation. Through this screen and subsequent studies, we identified three lead compound series. We have focused our attention on a pyridazine-based lead series. Importantly, a compound from this series has demonstrated profound efficacy in several disease models including Alzheimer’s disease, ALS and epilepsy. We are currently focused on 1) development of pyridazine compound series for human use, 2) uncovering the mechanism of compound action, 3) understanding the role of EAAT2 in the regulation of synaptic plasticity and function, and 4) evaluation of compounds in other disease models including depression and Gulf War illness.
Molecular biology: RT-PCR, Northern and Southern blotting, cDNA cloning, transfection, Western blotting, immunoprecipitation, cell fractionation, protein purification, ELISA
Cell Biology: cell culture, immunohistochemistry.
Transgenic: production and analysis of transgenic mice
Behavioral testing: motor function, cognitive functions, anxiety and depressive-like behaviors