Neuroprotective role of NFKB in HIV dementia

$266,631P01FY2002MHNIH

University Of Rochester, Rochester NY

Investigators

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Abstract

DESCRIPTION: (Provided by applicant): 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. Preliminary data presented in this proposal show that the cellular transcription factor NFKB 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 NFKB-mediated induction of genes, which negatively regulate programmed cell death. The experiments outlined in this proposal are intended to investigate the molecular mechanisms by which NFKB/Rel proteins exert their neuroprotective effects, and to determine the specific contribution of individual NFKB/Rel family members to this process. These studies will be conducted using well-characterized and appropriate neuronal model systems, and a representative array of candidate HIV-1 neurotoxins. Endogenous pathways of NFKB activation in neurons will also be examined, by using specific neurotrophins to activate this transcription factor, and a systematic investigation of NFKB-induced target genes will be performed, with an emphasis on genes involved in the regulation of apoptosis. Finally, the effects of NFKB activation on the caspase cascade will be examined, in neurons exposed to candidate HIV-1 neurotoxins, and in control cells. Taken together, these studies are expected to enhance our understanding of NFKB-mediated neuroprotection, and provide insights that may lead to the development of new therapeutic strategies for HIV-1 associated neurological disease.

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