Infection with the HIV-1 virus is associated with effects on both the central and peripheral nervous systems including the HIV-1 cognitive/motor syndrome and HIV-1 -related sensory neuropathies. In this grant proposal we shall investigate the mechanisms by which the HIV-1 virus can compromise the function of sensory neurons associated with pain. In our preliminary data we demonstrate that sensory (dorsal root ganglion, [DRG]) neurons express the CXCR4 as well as other chemokine receptors. Activation of these receptors by chemokines or by the HIV-1 coat protein gpl20 activates intracellular signaling pathways that produce neuronal excitation and pain. Gp120 also activates the JNK signaling pathway that ultimately produces neuronal apoptotic death. In the experiments discussed in this proposal we shall (1) further examine the role of the CXCR4 and other receptors in mediating the effects of gp120 on DRG neurons; (2) examine the interactions between chemokines, gpl20, anti-retroviral drugs and members of the JNK signaling pathway in compromising the function of sensory neurons; and (3) examine the mechanisms by which gpl20 produces activation of JNK and induces the death of DRG neurons. These results will help us to understand how the HIV-1 virus can compromise the functions of sensory neurons and suggest novel targets for therapeutic interventions in the treatment of HIV-1 -associated sensory neuropathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043095-03
Application #
6753562
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Nunn, Michael
Project Start
2002-07-19
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$344,763
Indirect Cost
Name
Northwestern University at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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