Ph.D. (1993) |
Sanjay
Maggirwar
Associate Professor of Microbiology & Immunology Primary Appointment: GEBS Cluster Affiliations: |
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| Contact Information: | ||
| University of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 672 Rochester, New York 14642 |
MRB Room 3-9645 (office) Phone: (585) 273-2276 E-Mail: sanjay_maggirwar@ urmc.rochester.edu |
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- Research Focus
- Role of NF-kappaB in Cell Growth and Survival
- Research Overview
- Inflammatory Mechanisms Associated with HIV-1 Dementia: HIV-1 associated dementia (HAD) is due in part to aberrant activation of brain resident macrophages and microglial cells by viral proteins, causing neuronal dysfunction and death over time. We are conducting experiments to understand better how macrophages and microglial cells are activated in HAD. We hypothesize that CD40 signaling in microglia and in brain microvascular endothelial cells (BMVEC) may synergize with the effects of candidate HIV-1 neurotoxins, such as Tat or platelet activating facotr (PAF), and play a pivotal role in HAD. To test this hypothesis, we are analyzing synergistic effects of candidate HIV-1 neurotoxins and CD40 engagement on inflammatory gene expression in human macrophages and microglial cells, by examining signaling mechanisms associated with CD40 engagement, including analyses of the anti-inflammatory effects of NF-kB inhibitors, minocycline and glitazones. In addition, we are examining the role of CD40 engagement in monocyte adhesion and migration through an artificial BBB in response to HIV-1 neurotoxins, by determining specific signaling events that lead to increased expression of adhesion and inflammatory molecules in human BMVEC. Additionally, we are testing whether down-modulation of CD40 expression, following CD40-specific RNA interference or exposure to pharamcologic inhibitors (statins), antagonizes cellular migration through BBB. Finally, our intentions are to use CD40 KO mice, CD40L KO mice or wild-type mice treated with a monoclonal antibody specific for mouse CD40L that disrupts CD40-CD40L interaction, to investigate whether the interplay between CD40- and HIV-1 neurotoxin-mediated signaling also contributes to the CNS inflammation and impaired synaptic transmission in vivo. Collectively, these investigations will identify novel therapeutic strategies that may enhance neuronal function and survival in neuroAIDS.
- Endogenous Mechanisms of Neuroprotection: HIV-1 associated neurologic disease is believed to be the result of a chronic inflammatory state, in which soluble neurotoxic molecules, of both viral and cellular origin, act to cause neuronal injury and dysfunction. We hypothesize that HIV-1 neurotoxicity is opposed by a number of endogenous pathways and mediators, which serve to protect neurons. For example, neurotrophins can augment neuronal survival and function through the activation of specific receptors (Trk receptors) and subsequent initiation of signaling cascades. We therefore propose to study endogenous neuroprotective pathways that may provide us with new therapeutic strategies for neuroAIDS. This will be achieved through two specific aims. In Aim 1, experiments will focus on signaling pathways associated with neurotrophin receptor activation, including analyses of the neuroprotective effects of inhibitors of mixed lineage kinases (MLK)-3, p38 kinase and c-Jun NH2 terminal kinases (JNK), as well as peptidomimetic Trk ligands. Effects on the survival and function of neurons exposed to candidate HIV-1 neurotoxins will be evaluated, as will effects on monocyte/microglial activation. In the second aim, we will evaluate the cell signaling events that are modulated in response to the inhibition of MLK-3, using both pharmacological and genetic approaches. These experiments will take advantage of available dominant negative mutants and MLK-3 knockout mice (to genetically target MLK-3), as well as extant pharmacologic compounds and new, highly specific MLK-3 blockers that will be developed by our commercial partner. Collectively, these investigations will identify novel neuroprotective strategies that may enhance neuronal function and survival in neuroAIDS. Results from these studies will be correlated with intracellular signaling events that occur in response to drug treatment, in order to identify new therapeutic targets.
- Recent Publications
- Chugh P, Bradel-Tretheway B, Monteiro-Filho CM, Planelles V, Maggirwar SB, Dewhurst S, Kim B Akt inhibitors as an HIV-1 infected macrophage-specific anti-viral therapy. Retrovirology. 2008;5:11
- Dewhurst S, Maggirwar SB, Schifitto G, Gendelman HE, Gelbard HA "Glycogen synthase kinase 3 Beta (GSK-3beta) as a therapeutic target in neuroAIDS." J Neuroimmune Pharmacol. 2007 Mar;2(1):93-6
- Sui Z, Sniderhan LF, Schifitto G, Phipps RP, Gelbard HA, Dewhurst S, Maggirwar SB "Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia." J Immunol. 2007 Mar 1;178(5):3226-36
- Thatcher TH, Maggirwar SB, Baglole CJ, Lakatos HF, Gasiewicz TA, Phipps RP, Sime PJ. "Aryl Hydrocarbon Receptor-Deficient Mice Develop Heightened Inflammatory Responses to Cigarette Smoke and Endotoxin Associated with Rapid Loss of the Nuclear Factor-{kappa}B Component RelB." Am J Pathol. 2007 Mar;170(3):855-64.
- Wang J, Gigliotti F, Bhagwat SP, Maggirwar SB, Wright TW. "Pneumocystis
Stimulates MCP-1 Production by Alveolar Epithelial Cells through a
JNK-dependent Mechanism." Am J Physiol Lung Cell Mol Physiol.
2007 Feb 16;
- Chugh P, Fan S, Planelles V, Maggirwar SB, Dewhurst S, Kim B "Infection of Human Immunodeficiency Virus and Intracellular Viral Tat Protein Exert a Pro-survival Effect in a Human Microglial Cell Line." J Mol Biol. 2006 Nov 10;
- Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernández JA, Larue B, Griffin JH, Chopp M, Zlokovic BV "Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage." Nat Med. 2006 Oct 29;
- Ray DM, Morse KM, Hilchey SP, Garcia TM, Felgar RE, Maggirwar SB, Phipps RP, Bernstein SH "The novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) induces apoptosis of human diffuse large B-cell lymphoma cells through a peroxisome proliferator-activated receptor gamma-independent pathway." Exp Hematol. 2006 Sep;34(9):1201-1210
- Sui Z, Fan S, Sniderhan L, Reisinger E, Litzburg A, Schifitto G, Gelbard HA, Dewhurst S, Maggirwar SB "Inhibition of mixed lineage kinase 3 prevents HIV-1 Tat-mediated neurotoxicity and monocyte activation." J Immunol. 2006 Jul 1;177(1):702-11
- Sui Z, Sniderhan LF, Fan S, Kazmierczak K, Reisinger E, Kovács AD, Potash MJ, Dewhurst S, Gelbard HA, Maggirwar SB "Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons." Eur J Neurosci. 2006 May;23(10):2623-34
- Sui Z, Kovacs AD, Maggirwar SB. "Recruitment of active glycogen synthase kinase-3 into neuronal lipid rafts." Biochem Biophys Res Commun. 2006 May 24;
- Yang SR, Chida AS, et al. "Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and post-translational modifications of histone deacetylase in macrophages." Am J Physiol Lung Cell Mol Physiol. 2006 Feb 10;
- Jin, N., A. D. Kovacs, et al. "Opposite effects of lithium and valproic acid on trophic factor deprivation-induced glycogen synthase kinase-3 activation, c-Jun expression and neuronal cell death." Neuropharmacology 48(4): 576-83, 2005.
- Wang, J., F. Gigliotti, et al. "Pneumocystis carinii activates the NF-kappaB signaling pathway in alveolar epithelial cells." Infect Immun 73(5): 2766-77, 2005.
- Kovacs AD, Chakraborty-Sett S, Ramirez SH, Sniderhan LF, Williamson AL, Maggirwar SB. Mechanism of NF-kappaB inactivation induced by survival signal withdrawal in cerebellar granule neurons. Eur J Neurosci. 20:345-52, 2004.
- Ramirez SH, Fan S, Maguire CA, Perry S, Hardiek K, Ramkumar V, Gelbard HA, Dewhurst S, Maggirwar SB. Activation of adenosine A2A receptor protects sympathetic neurons against nerve growth factor withdrawal. J Neurosci Res. 77:258-69, 2004.
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