The mechanisms by which human immunodeficiency virus type-1 effects neural injury in HIV-associated dementia (HAD) remain largely unknown. It is thought that the HIV-1 envelope glycoprotein gp120 plays a role in the syndrome by inducing neurotoxicity, mediated in part by the undue glial secretion of tumor necrosis factor alpha and other potentially neurotoxic cytokines. PKR is an important pro-apoptotic kinase induced by TNF that triggers programmed cell death in a variety of cell types in response to stress signals. It has also been shown that PKR activates certain target molecules that are identical to those reported to be activated in gp120-induced neuronal cell death, such as p53 and NF-kappaB. Recent experiments that I have performed suggest that PKR is expressed at a low level in cultured cerebrocortical neurons, and it is significantly upregulated in response to gp120 treatment. Furthermore, I demonstrated that the inactivation of PKR in this culture is able to protect neurons against gp120 exposure. On the basis of these observations and other evidence, I propose to characterize and functionally validate the role of PKR in gp120-induced neurotoxicity and to elucidate the effector pathways by which it exerts its potentially destructive effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS048767-01A1
Application #
6886580
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Nunn, Michael
Project Start
2004-12-01
Project End
2005-06-15
Budget Start
2004-12-01
Budget End
2005-06-15
Support Year
1
Fiscal Year
2005
Total Cost
$22,914
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Alirezaei, Mehrdad; Fox, Howard S; Flynn, Claudia T et al. (2009) Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis. Autophagy 5:152-8
Alirezaei, Mehrdad; Kiosses, William B; Flynn, Claudia T et al. (2008) Disruption of neuronal autophagy by infected microglia results in neurodegeneration. PLoS One 3:e2906
Alirezaei, Mehrdad; Watry, Debbie D; Flynn, Claudia F et al. (2007) Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons. J Neurosci 27:11047-55