The CNS remains a target of HIV in the era of HAART, and the effects of CNS dysfunction can be devastating. The SIV-infected monkey model for HlV-related diseases has been invaluable in studies of HIV/AIDS pathogenesis and treatment/vaccine research. We and others have developed systems and techniques to enable the study of CNS disease in SIV-infected monkeys. Using brain RNA from different stages of SIV-induced disease, we have found distinct alterations in the transcriptional profile both during the stable phase of disease, when animals are generally asymptomatic but have measurable CNS functional abnormalities, as well as in end-stage neurological disease. Here, we will first investigate 2 mechanisms for neuronal damage identified from alterations in neuronal gene expression in microarray studies. Second, using a recently developed HAART protocol, we will now study CNS function and changes in CNS gene expression during HAART treatment of SIV-infected monkeys. Furthermore, we have developed methodologies for metabolomic analysis, enabling us to perform a longitudinal study to identify significant biomarkers in plasma and CSF that correlate with CNS disease. These experiments will yield novel data, and lead to the identification of unique molecules that can then be examined in humans, as well as provide the starting point for new studies aimed at the sources of the identified metabolic differences. The identification of molecular markers for neuroAIDS is valuable for both diagnostic and etiopathogenic reasons, and we believe the recent developments in metabolomics give these techniques a distinct advantage in achieving this goal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073490-03
Application #
7169867
Study Section
Special Emphasis Panel (ZMH1-BRB-S (11))
Program Officer
Joseph, Jeymohan
Project Start
2005-02-10
Project End
2010-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$440,667
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Villeneuve, Lance M; Purnell, Phillip R; Stauch, Kelly L et al. (2016) HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution. J Neurovirol 22:564-574
Villeneuve, Lance M; Purnell, Phillip R; Boska, Michael D et al. (2016) Early Expression of Parkinson's Disease-Related Mitochondrial Abnormalities in PINK1 Knockout Rats. Mol Neurobiol 53:171-186
Marcondes, Maria Cecilia G; Morsey, Brenda; Emanuel, Katy et al. (2015) CD8+ T cells maintain suppression of simian immunodeficiency virus in the central nervous system. J Infect Dis 211:40-4
Stauch, Kelly L; Purnell, Phillip R; Villeneuve, Lance M et al. (2015) Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism. Proteomics 15:1574-86
Yelamanchili, Sowmya V; Lamberty, Benjamin G; Rennard, Deborah A et al. (2015) MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease. PLoS Pathog 11:e1005032
Villeneuve, Lance M; Stauch, Kelly L; Fox, Howard S (2014) Proteomic analysis of the mitochondria from embryonic and postnatal rat brains reveals response to developmental changes in energy demands. J Proteomics 109:228-39
Stauch, Kelly L; Purnell, Phillip R; Fox, Howard S (2014) Quantitative proteomics of synaptic and nonsynaptic mitochondria: insights for synaptic mitochondrial vulnerability. J Proteome Res 13:2620-36
Marcondes, Maria Cecilia Garibaldi; Ojakian, Ryan; Bortell, Nikki et al. (2014) Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin. Mediators Inflamm 2014:358218
Sabouri, Amir H; Marcondes, Maria Cecilia Garibaldi; Flynn, Claudia et al. (2014) TLR signaling controls lethal encephalitis in WNV-infected brain. Brain Res 1574:84-95
Purnell, Phillip R; Fox, Howard S (2014) Efavirenz induces neuronal autophagy and mitochondrial alterations. J Pharmacol Exp Ther 351:250-8

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