Microglia (MG) are resident immunocompetent phagocytic cells strongly linked to the pathogenesis of HIV-1- associated neurocognitive disorders (HAND). HIV-1 brain infection triggers MG activation and neuroinflammatory responses reflective of the production of pro-inflammatory factors that elicit neuronal dysfunction and death. To date, there is considerable interest in strategies that modulate MG-associated inflammation and research on identification of specific target(s) in controlling MG neurotoxic activities is imperative. It is well-known that MG express a variety of ion channels and the voltage-gated K+ (Kv) channels have recently gained attention as promising targets for therapy of neurological disorders. Nonetheless, there is very limited information available on how Kv channels can be "best" utilized for therapeutic benefit. To this end, we seek funds to study the role of Kv channels, specifically the Kv1.3, in HIV-1-induced MG activation, migration, production of neurotoxins, resultant neurotoxicity and consequent HAND pathogenesis. Electrophysiological, pharmacological, molecular and immunocyto(histo)chemical techniques will examine the role of Kv1.3 in regulating MG function in laboratory and animal models of human disease.
In specific aim 1 we will determine involvement of Kv1.3 channels in HIV-1gp120- and virus-induced MG activation, migration, resultant neurotoxic activity and their potential signaling pathways.
In specific aim 2 we will assess the role of Kv1.3 in MG-induced neuronal dysfunction/injury and cognitive impairment in a murine model of neuroAIDS and explore therapeutic potential of Kv channel antagonists in this animal model. Overall, these studies focus on not only understanding the role(s) that Kv1.3 might play in MG-associated neurotoxic activity and HAND pathogenesis, but also identifying potential target(s) for the development of therapeutic strategies. If successful, these studies will provide a proper roadmap for expected efficacy of Kv channel antagonists in ameliorating HIV-1-induced brain injury.

Public Health Relevance

This grant proposal studies how HIV-1 triggers microglia activation, migration and production of neurotoxins, resulting in neuronal dysfunction and death via microglia voltage-gated Kv1.3 channel and explores microglia Kv1.3 channel as a potential target for development of therapeutic strategies.

National Institute of Health (NIH)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Wong, May
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University of Nebraska Medical Center
Schools of Medicine
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Liu, Jianuo; Xu, Peng; Collins, Cory et al. (2013) HIV-1 Tat protein increases microglial outward K(+) current and resultant neurotoxic activity. PLoS One 8:e64904
Martinez-Skinner, Andrea L; Veerubhotla, Ram S; Liu, Han et al. (2013) Functional proteome of macrophage carried nanoformulated antiretroviral therapy demonstrates enhanced particle carrying capacity. J Proteome Res 12:2282-94