HIV invades the brain shortly after infection and induces neuropathologies including astrocytosis, neuronal impairment and abnormal glutamatergic signaling. Glutamate excitotoxicity results from elevated extracellular glutamate leading to over activation of glutamate receptors and is implicated in HIV-Associated Neurocognitive Disorders (HAND). We show that Wnt/-catenin signaling regulates a number of proteins involved in astrocytic glutamate cycling. Further, our lab has previously identified a number of inflammatory mediators (e.g HIV Tat and IFNg) that disrupt the Wnt/-catenin pathway in astrocytes. Because Wnt/-catenin signaling regulates proteins responsible for cell structure, synaptic activity, cell proliferation, and survival, we propose that disrupted -catenin signaling in astrocytes will negatively impact astrocyte-neuronal communication. Our central hypothesis is that i) inhibition of -catenin by inflammatory mediators (IFN?) and HIV in astrocytes will induce structural (cell morphology) and functional (synaptic activity, clearing mechanisms) deficits associated with HAND and ii) -catenin signaling will regulate key proteins necessary for glutamate clearance and can protect against glutamate excitotoxicity. To this end, we will determine the impact of diminished Wnt/ catenin signaling in astrocytes on neuronal injury in vitro and in vivo (Aim 1) and determine the mechanism by which -catenin signaling regulates excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS) in astrocytes (Aim 2). Collectively, these studies will provide insight into HIV-mediated dysregulation of astrocyte-neuronal communication through Wnt/-catenin signaling. A better understanding of the interplay between these factors will lead to novel therapeutic strategies to combat the growing incidence of HAND.
HIV invades the brain within one week of infection and leads to a spectrum of neurologic complications including astrocytosis and neuronal dysfunction. Glutamate cycling dysregulation results from abnormal astrocyte function and contributes to neuronal injury in part due to disruptions in astrocyte-neuronal communication. We have identified the Wnt/?-catenin signaling pathway as one key regulator for glutamate cycling proteins. We propose to study the molecular mechanisms by which this occurs and the impact of Wnt/?-catenin signaling in astrocytes on neuronal function. Understanding these pathways will lead to novel therapeutic breakthroughs in glutamate-mediated disorders including HIV.
| Lutgen, Victoria; Narasipura, Srinivas D; Sharma, Amit et al. (2016) ?-Catenin signaling positively regulates glutamate uptake and metabolism in astrocytes. J Neuroinflammation 13:242 |
