Research
Project 1: Polarity determinants in synaptic stability and plasticity
The stability and plasticity of synapses are both important for cognitive functions. Plasticity is necessary for learning, while stably formed synapses are believed to encode for long term memory. Yet it is unclear how neurons can maintain this delicate balance and achieve both stability and plasticity in synapses just a few microns apart. Clearly, a high level of compartmentalization is required, which makes polarity proteins ideal candidates to function in this capacity, as they serve to separate and maintain distinct membrane domains. Our lab found that a class of polarity proteins called Par (partitioning defective) proteins plays a key role in dendritic spine morphogenesis and plasticity. We are currentlyl further examining the role of these Par proteins in synaptic stability and plasticity, using advanced molecular imaging techniques combined with biochemical and behavioral analyses.
Project 2: Polarity determinants in endolysosomal trafficking and proteostasis
The vast majority of Alzheimer’s disease (AD) is sporadic, with aging being the biggest risk factor. Yet age-related changes within neurons that can drive the AD pathogenic process remain elusive. AD is characterized by plaques composed of β-amyloid (Aβ), which is derived from amyloid precursor protein (APP) through cleavage by β- and γ-secretases. The rate-limiting step of Aβ generation is the convergence between APP and its β-secretase BACE1. Interestingly, our lab found Par3 expression is significantly reduced by middle-age, and loss of Par3 is common in human AD brains. In addition, Par3 depletion causes a significant increase in APP and BACE1 convergence. We are currently aiming to further establish the molecular mechanisms by which Par polarity proteins are involved in AD pathogenesis using conditional knockout mouse models.
Project 3: Cellular and molecular mechanisms underlying post-traumatic epilepsy
Post-traumatic epilepsy (PTE) is a recurrent seizure disorder due to brain trauma. The incidence of PTE is highest in adolescents and young adults partly due to their susceptibility to brain trauma in sports, motor vehicle and military-related incidents. The still-developing brains of adolescents also present a unique challenge for therapeutic interventions as the developing brain exhibits a distinctive injury response than the adult brain. Thus, there is an urgent need for research into adolescent PTE and potential remediation. In collaboration with Drs. Mladen-Roko Rasin and David Crockett in our department, we are currently examining the cellular and molecular mechanisms underlying adolescent TBI and PTE with the goal of developing effective therapies.