Chemokines are a family of small proteins that are known to play an important role as messengers in the immune system. Chemokines exert their effects through the activation of a family of G-protein coupled receptors (GPCRs). It is also known that some of these GPCRs can act as receptors for the HIV-1 virus and are key elements in the ability of the virus to infect cells of the immune system. Chemokine receptors have also been found in the brain, however nothing is known about their cellular functions or how neuronal chemokine receptors may contribute to HIV-1 associated neuropathology or interact with other endogenous systems such as those for opioids. We have recently shown that neuronal chemokine receptors can produce effects on neurons typical of other GPCRs, including rapid changes in synaptic communication. Moreover, some chemokines can block neuronal apoptosis induced by the HIV-1 coat glycoprotein gp120. In the present proposal we shall extend these findings and ask the following questions: 1. What are the mechanisms underlying chemokine induced changes inn synaptic communication? How does neuronal chemokine receptor activation produce changes in neuronal Ca and other ion channels? 2. What is the range of chemokine effects in the nervous system? Which neurons are chemokine sensitive and to which chemokines? 3. What is the mechanism of the anti-apoptotic effects of chemokines? How do chemokines activate the anti-apoptotic enzyme Akt? 4. What is the range of survival effects mediated by chemokines? Are chemokines effective in different models of neurodegenerative disease? In order to carry out these studies we shall utilize a variety of electrophysiological, imaging, biochemical and molecular biological techniques. These studies will help us ascertain how chemokines regulate neuronal communication and excitability and how chemokine receptors may contribute to the neuropathological correlates of HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013141-04
Application #
6634293
Study Section
Special Emphasis Panel (ZRG1-AARR-5 (01))
Program Officer
Sharp, Charles
Project Start
2000-04-01
Project End
2005-02-28
Budget Start
2003-03-01
Budget End
2004-02-29
Support Year
4
Fiscal Year
2003
Total Cost
$322,971
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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