Maggirwar Lab

Research Focus: Regulation of Neuronal Survival

Roll of NF-kB in neuronal survival

Rel protects cells from apoptosis. (Graph)

Severe neurologic complications, including HIV-associated dementia (HAD), occur in a significant proportion of HIV-1 infected individuals. HAD is marked by cognitive and motor deficits, and pathologic correlates of this syndrome include neuronal apoptosis. Neuronal cell death and damage in HIV-1 infected individuals are thought to be induced by a number of soluble neurotoxic factors, of both viral and cellular origin. Molecular pathways which may protect neurons from the deleterious effects of these candidate HIV-1 neurotoxins remain poorly understood.

Our previous studies have shown that the cellular transcription factor NF-kB may protect neurons from the pro-apoptotic effects of candidate HIV-1 neurotoxins. Our data further suggest that this may occur as a result of NF-kB-mediated induction of genes which negatively regulate programmed cell death. Experiments which are ongoing in our laboratory are intended to investigate the molecular mechanisms by which NF-kB/Rel proteins exert their neuroprotective effects, and to determine the specific contribution of individual NF-kB/Rel family members to this process. These studies are being conducted using well-characterized and appropriate neuronal model systems, and a representative array of candidate HIV-1 neurotoxins. We are also examining the protective effect of NF-kB on neurotrophin-dependent sympathetic neurons, following neurotrophin deprivation (which initiates a well-defined apoptotic program in these cells).

Glial cells infected with GFP-expressing adenovirus

Endogenous pathways of NF-kB activation in neurons are also being examined, by using secific neurotrophins to activate this tranpscription factor, and a systematic investigation of NF-kB-induced target genes will be performed, with an emphasis on genes involved in the regulation of apoptosis. Finally, the effects of NF-kB activation on the caspase cascade are being examined, in neurons exposed to candidate HIV-1 neurotoxins, and in control cells. Taken together, these studies are expected to enhance our understanding of NF-kB-mediated neuroprotection, and provide insights that may lead to the development of new therapeutic strategies for HIV-1 associated neurological disease.

Role of GSK-3b in PAF-mediated neurotoxicity

Platelet activating factor (PAF) is a well-characterized candidate HIV-1 neurotoxin which exerts potent effects on neuronal survival and neuronal migration. PAF also activates the enzyme glycogen synthase kinase (GSK)-3b in neurons, a enzyme previously implicated in regulation of cell survival and cytoskeletal rearrangement. We are presently examining how GSK-3b may contribute to PAF's effects on neurons.

Tat- and PAF- Mediated Neurotoxicity is blocked by Lithium

For a list of publications, please click here.

Sanjay Maggirwar
Associate Professor of
Microbiology & Immunology

Contact Information:

University of Rochester
School of Medicine
and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642

Phone: (585) 273-2276
Fax: (585) 473-9573