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.
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.
|Reiner, Benjamin; Wang, Wenwei; Liu, Jianuo et al. (2016) Platelet-activating factor attenuation of long-term potentiation in rat hippocampal slices via protein tyrosine kinase signaling. Neurosci Lett 615:83-7|
|Liu, Han; Xu, Enquan; Liu, Jianuo et al. (2016) Oligodendrocyte Injury and Pathogenesis of HIV-1-Associated Neurocognitive Disorders. Brain Sci 6:|
|Mosley, R Lee (2015) Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders. J Neuroimmune Pharmacol 10:522-7|
|Kiyota, Tomomi; Morrison, Christine M; Tu, Guihua et al. (2015) Presenilin-1 familial Alzheimer's disease mutation alters hippocampal neurogenesis and memory function in CCL2 null mice. Brain Behav Immun 49:311-21|
|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|
|Ton, Hoai; Xiong, Huangui (2013) Astrocyte Dysfunctions and HIV-1 Neurotoxicity. J AIDS Clin Res 4:255|
|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|
|Liu, Han; Liu, Jianuo; Liang, Shangdong et al. (2013) Plasma gelsolin protects HIV-1 gp120-induced neuronal injury via voltage-gated K+ channel Kv2.1. Mol Cell Neurosci 57:73-82|
|Liu, J; Xu, C; Chen, L et al. (2012) Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity. Cell Death Dis 3:e254|