The present proposal stems from research conducted during previous funding periods that revealed novel and unexpected roles of the chemokine CXCL12, and its primary receptor CXCR4, on central neurons and glia. Specifically, the objectives of this proposal are to characterize the effect of CXCL12 on dendritic spines, which are critically involved in neuroprotection and synaptic plasticity, and to study the modulation of this effect by opiates and HIV proteins. The proposed studies will characterize the molecular mechanisms involved in the dendritic spine changes evoked by CXCL12;determine the effect of opiates and HIV proteins on CXCL12-induced changes;and establish the potential behavioral consequences of these alterations in the context of HIV neuropathology and drug abuse. This will be accomplished using both in vitro and in vivo approaches and various techniques of cellular/molecular neurobiology and behavior. The long-term goal of this research is to identify pharmacological targets for adjuvant neuroprotective treatments that may be used to reduce neurological problems in HIV patients, thus assisting in the clinical management of populations at high risk of neuropathology, such as intravenous drug users. The studies proposed in aim 1 will provide detailed information about the kinetics and mechanisms involved in CXCL12-induced dendritic spine changes and confirm the role of the CXCL12/CXCR4 axis in the regulation of spines in vivo (with a major focus on the prefrontal cortex and hippocampus). We expect the results to support the hypothesis that CXCL12 regulates expression of gene programs that control synapse number, which ultimately results in more spines. Overall, these experiments intend to confirm the role of CXCL12/CXCR4 in maintenance of a healthy dendritic arbor and to inform some of the analysis to be conducted in aim 2 and 3. The experiments in aim 2 are important to determine if morphine and HIV viral proteins (or cellular factors induced by these proteins) affect the CXCL12 regulation of dendritic spines. Along with the results from aim 3, these findings will indicate whether morphine and HIV can precipitate neuronal damage by inhibiting normal function of this homeostatic chemokine. Finally, studies in aim 3 will unveil subtle but important differences in behavioral performance (involving the prefrontal cortex and hippocampus) between WT and HIV-Tg rats that will help us characterize the specific deficits associated with expression of HIV viral proteins in the brain as well as impairment of CXCR4 function caused by morphine/CXCR4 antagonists.

Public Health Relevance

Despite the benefits of current antiretroviral treatments, the neurological complications of HIV infection, which include both neurocognitive and motor/sensory deficits, remain an unmet medical and social need - partly because the biological bases of these complex disorders are still undefined. The studies proposed in this application aim to identify pharmacological targets for adjuvant neuroprotective treatments that may be used to reduce neurological problems in HIV patients, thus assisting in the clinical management of populations at high risk of neuropathology, such as intravenous drug users.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA015014-11
Application #
8498835
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Sorensen, Roger
Project Start
2001-09-28
Project End
2018-04-30
Budget Start
2013-08-15
Budget End
2014-04-30
Support Year
11
Fiscal Year
2013
Total Cost
$309,000
Indirect Cost
$109,000
Name
Drexel University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Nash, Bradley; Meucci, Olimpia (2014) Functions of the chemokine receptor CXCR4 in the central nervous system and its regulation by ?-opioid receptors. Int Rev Neurobiol 118:105-28
Strazza, Marianne; Banerjee, Anupam; Alexaki, Aikaterini et al. (2014) Effect of ?-opioid agonist DAMGO on surface CXCR4 and HIV-1 replication in TF-1 human bone marrow progenitor cells. BMC Res Notes 7:752
Pitcher, Jonathan; Abt, Anna; Myers, Jaclyn et al. (2014) Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction. J Clin Invest 124:656-69
Pedrazzi, Manuela; Nash, Bradley; Meucci, Olimpia et al. (2014) Molecular features contributing to virus-independent intracellular localization and dynamic behavior of the herpesvirus transport protein US9. PLoS One 9:e104634
Pitcher, Jonathan; Wurth, Roberto; Shimizu, Saori et al. (2013) Multispectral imaging and automated laser capture microdissection of human cortical neurons: a quantitative study of CXCR4 expression. Methods Mol Biol 1013:31-48
Banerjee, Anupam; Strazza, Marianne; Wigdahl, Brian et al. (2011) Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis. J Neurovirol 17:291-302
Shimizu, Saori; Abt, Anna; Meucci, Olimpia (2011) Bilaminar co-culture of primary rat cortical neurons and glia. J Vis Exp :
Shimizu, Saori; Brown, Michael; Sengupta, Rajarshi et al. (2011) CXCR7 protein expression in human adult brain and differentiated neurons. PLoS One 6:e20680
Abt, Anna Cook; Meucci, Olimpia (2011) Regulation of neuronal ferritin heavy chain, a new player in opiate-induced chemokine dysfunction. J Neuroimmune Pharmacol 6:466-76
Khan, Muhammad Z; Vaidya, Avinash; Meucci, Olimpia (2011) CXCL12-mediated regulation of ANP32A/Lanp, a component of the inhibitor of histone acetyl transferase (INHAT) complex, in cortical neurons. J Neuroimmune Pharmacol 6:163-70

Showing the most recent 10 out of 29 publications