This Project will test the hypothesis that activation of NFkB in microglia, and in cells that constitute the blood-brain barrier (BBB), may contribute to the neuropathogenesis of AIDS, and the blockade of NFkB may have therapeutic potential in this setting. The following Specific Aims are proposed. (1) Examine whether persistent NFkB activation is correlated with the release of neurotoxins from, or HIV-1 replication in, microglia. Experiments will also be conducted to test directly whether NFkB activation leads to production of neurotoxins by microglia, and whether specific blockade of NFkB leads to inhibition of the release of neurotoxins from, or HIV-1 replication 1, microglia. (2) Employ cell culture models for the BBB (brain microvascular endothelial cells [BMVECs] and astrocytes) to test the hypothesis that activation of NFkB in cells that comprise the BBB may result in damage to the integrity of this barrier. Experiments will determine whether NFkB activation leads to increased expression of adhesion molecules or metallo-proteases by MBVECs and astrocytes, and studies will also be conducted to test whether induction of these proteins by TNF-alpha is prevented by specific blockade of NFkB. In addition, analogous experiments will be conducted using in vitro assays for BBB integrity. Specifically, the integrity of MMVEC and BMVEC/astrocyte monolayers will be assessed by measuring their permeability to macromolecules and by quantitating trans-monolayer migration by monocytes. (3) Test broadly-based anti-oxidant and anti- inflammatory drugs for their ability to block NFkB activation in microglia and in BMVECs. Data from these studies will be correlated with effects on neurotoxin release (microglia) and adhesion molecule and metalloprotease expression (BMVECs). Taken together, these experiments are expected to result in the identification of novel therapeutic strategies for the treatment of HIV-1 dementia.
| Stone, David K; Kiyota, Tomomi; Mosley, R Lee et al. (2012) A model of nitric oxide induced ?-synuclein misfolding in Parkinson's disease. Neurosci Lett 523:167-73 |
| Gong, Nan; Liu, Jianuo; Reynolds, Ashley D et al. (2011) Brain ingress of regulatory T cells in a murine model of HIV-1 encephalitis. J Neuroimmunol 230:33-41 |
| Mosley, R Lee; Gendelman, Howard E (2010) Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders. Exp Neurol 222:1-5 |
| Kraft-Terry, Stephanie D; Stothert, Andrew R; Buch, Shilpa et al. (2010) HIV-1 neuroimmunity in the era of antiretroviral therapy. Neurobiol Dis 37:542-8 |
| Huang, Xiuyan; Reynolds, Ashley D; Mosley, R Lee et al. (2009) CD 4+ T cells in the pathobiology of neurodegenerative disorders. J Neuroimmunol 211:3-15 |
| Nowacek, Ari; Kosloski, Lisa M; Gendelman, Howard E (2009) Neurodegenerative disorders and nanoformulated drug development. Nanomedicine (Lond) 4:541-55 |
| Nowacek, Ari S; Miller, Reagan L; McMillan, Joellyn et al. (2009) NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery. Nanomedicine (Lond) 4:903-17 |
| Kadiu, Irena; Wang, Tong; Schlautman, Joshua D et al. (2009) HIV-1 transforms the monocyte plasma membrane proteome. Cell Immunol 258:44-58 |
| Kraft-Terry, Stephanie D; Buch, Shilpa J; Fox, Howard S et al. (2009) A coat of many colors: neuroimmune crosstalk in human immunodeficiency virus infection. Neuron 64:133-45 |
| Eggert, Dawn; Dash, Prasanta K; Serradji, Nawal et al. (2009) Development of a platelet-activating factor antagonist for HIV-1 associated neurocognitive disorders. J Neuroimmunol 213:47-59 |
Showing the most recent 10 out of 36 publications
