|
Regulation of Neuronal Survival
Role of NF-kB in neuronal survival
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).
Endogenous pathways of NF-kB activation in neurons are also being examined, by using specific
neurotrophins to activate this transcription 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.
|
Glial cells infected with GFP-expressing adenovirus
|
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.
|
