It is becoming increasingly clear that HIV-1 infection and drug abuse are interlinked epidemics. In fact, cocaine, often abused by HIV-1 infected patients, has been suggested to hasten as well as worsen disease pathogenesis, HIV-1 associated neurological disorders (HAND) are primarily a result of increased glial activation, and neuroinflammation, in response to HIV protein mediated release of toxic factors in the CNS. Among the known mediators induced in the CNS, we have identified platelet-derived growth factors (PDGF) in our microarray analysis as a factor associated with HAND. More recently, PDGF released from the astrocytes proximal to the endothelial cells as a cerebrovascular permeant in neurodegenerative disorder such as stroke. Additionally, cocaine has been implicated as a factor that disrupts the blood brain barrier. Based on these findings we hypothesized that Tat and/or cocaine mediated induction of PDGF-BB from both the astrocytes and their neighboring endothelial cells, could lead to enhanced disruption of the endothelial barrier resulting in increased pathology of HAND in HIV-1 infected cocaine abusers. To address this hypothesis two specific aims are proposed: 1) Investigate the molecular mechanisms involved in Tat/cocaine-mediated expression of PDGF in astrocytes and endothelial cells and, 2) To test the therapeutic potential of PDGF neutralizing antibody as an intervention strategy in vivo using two complementary murine models of HAND exposed to cocaine. These studies are both novel and innovative in that the role of PDGF as a mediator of HIV Tat and cocaine toxicity has never been explored before and furthermore, the efficacy of testing PDGF neutralizing antibody can have far reaching implications for HAND patients that are cocaine-abusers.

Public Health Relevance

HIV-1 infected individuals that abuse cocaine have increased risk of vascular changes that can result in increased complications of the CNS. This study proposes to explore how cocaine and HIV proteins together can increase the burden of a toxic mediator in the CNS and also aims to develop therapeutic interventions to inhibit vascular changed associated with cocaine and HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA033614-02
Application #
8334487
Study Section
Special Emphasis Panel (ZAI1-EB-A (J1))
Program Officer
Khalsa, Jagjitsingh H
Project Start
2011-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$200,436
Indirect Cost
$65,462
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198