Sanjay Balkrishna Maggirwar, M.B.A., Ph.D.

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1. Research Projects in Progress

We are interested in studying abilities of certain cellular proteins to promote survival of neurons exposed to the conditions that mimic disease states. Understanding of intrinsic survival mechanisms in neurons could be highly important in development of new therapeutic strategies for neurological diseases.

A. 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 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 factor (PAF), and play a pivotal role in HAD. We will investigate this in three specific aims. In Aim 1, we will analyze 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-kappaB inhibitors, minocycline and glitazones. In Aim 2, we will examine 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 will determine whether down-modulation of CD40 expression, following CD40-specific RNA interference or exposure to pharamcologic inhibitors (statins), antagonizes cellular migration through BBB. Finally, in Aim 3, we will 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.

B. Endogenous mechanisms of neuroprotection: This project uses in vitro rodent and human models to investigate how mixed lineage kinases,(MLKs), acting on pro-apoptotic c-Jun NH2 terminal kinase (JNK), are involved in the activation of mononuclear phagocytes and damage to synaptic architecture. Additionally, this project investigates the functional consequences of MLK3 inhibition in ex vivo brain tissue slices and tests the efficacy of new compounds, synthesized by Biofocus, LTD that inhibit MLK3, to deactivate mononuclear phagocytes, preserve synaptic architecture, and restore synaptic transmission during exposure to HIV-1 neurotoxins.

C. Crosstalk between GSK3beta and NF-kappaB signaling pathway: The overlap between NF-kappaB signaling events and GSK3beta regulation suggests that GSK3beta may be involved in NF-kappaB signaling and that disregulation of GSK3beta activity could potentially disrupt the NF-kappaB response, leading to cell death. Based on this notion, we are investigating, (1) whether HIV toxin Tat-mediated activation of GSK3beta is capable of disrupting activation of endogenous NF-kappaB,; and (2) since overexpression of NF-kappB can prevent cell death induced by Tat, whether it also is able to override toxic effects of irregular activation of GSK3beta.

Current Appointments

• Associate Professor - Department of Microbiology and Immunology (SMD)

Education
PhD Biochemistry	India-Univ of Pune, Pune	1993
MBA Marketing	India-Marathwada Univ, Aurangabad	1986
MS Biochemistry	India-Marathwada Univ, Aurangabad	1984
BS Biochemistry	India-Marathwada Univ, Aurangabad	1982

Post-Doctoral Training & Residency
Postdoctoral Fellow, Department of Microbiology and Immunology, Pennsylvania State University, College of Medicine, Hershey, PA.	1995 - 1997
Postdoctoral Fellow, Department of Pharmacology and Toxicology, Southern Illinois University, Springfield, IL.	1993 - 1994

Lab Website

http://www.urmc.rochester.edu/smd/mbi/faculty/labs/maggirwar/index.htm

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Recent Journal Articles
Showing the 5 most recent journal articles. (50 available)
Schifitto G; Zhong J; Gill D; Peterson DR; Gaugh MD; Zhu T; Tivarus M; Cruttenden K; Maggirwar SB; Gendelman HE; Dewhurst S; Gelbard HA. "Lithium therapy for human immunodeficiency virus type 1-associated neurocognitive impairment." Journal of neurovirology. 2009; 15(2):176-86.
Sniderhan LF; Garcia-Bates TM; Burgart M; Bernstein SH; Phipps RP; Maggirwar SB. "Neurotrophin signaling through tropomyosin receptor kinases contributes to the survival and proliferation of Non-Hodgkin Lymphoma." Experimental hematology. 2009; Epub 2009 Aug 27.
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. Epub 2008 Jan 31.
Yang SR; Valvo S; Yao H; Kode A; Rajendrasozhan S; Edirisinghe I; Caito S; Adenuga D; Henry R; Fromm G; Maggirwar S; Li JD; Bulger M; Rahman I. "IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung." American journal of respiratory cell and molecular biology. 2008; 38(6):689-98. Epub 2008 Jan 31.
Sniderhan LF; Stout A; Lu Y; Chao MV; Maggirwar SB. "Ankyrin-rich membrane spanning protein plays a critical role in nuclear factor-kappa B signaling." Molecular and cellular neurosciences. 2008; 38(3):404-16. Epub 2008 Apr 16.