We propose to use quantitative proteomics approaches to study the interactions between simianimmunodeficiency virus (SIV) and methamphetamine (METH) in the central nervous system (CNS) of rhesusmonkeys. This proposal builds on our previous works for examining the SIV infected brains of rhesusmonkeys for biomarker discovery using transcriptomics (gene array) and metabolomics (mass spectrometry)based technologies. For this project, we will perform hypothesis-based studies building on the wealth of datagenerated in functional proteomics at the University of Nebraska Medical Center (UNMC, Drs. HowardGendelman, Project 1 and Pawel Ciborowski, Project 3). Our working hypothesis is that in the presenceof METH, the harmful effects of SIV on the CNS are increased: when SIV and METH are joined thereare dual and interacting untoward effects on CNS function and neuronal viability. Furthermore, sincethe proteome is broadly affected during disease, we believe that the use proteomics methodologiesin the rhesus monkey/SIV/METH model will enable us to explore distinct and synergistic CNS diseasemechanisms. We will utilize both unbiased and directed approaches to study how the effects of SIV on theprimate brain are affected by METH. These studies are designed to utilize optimal samples for suchdiscovery and follow-up validation, minimizing experimental confounds and directly studying the targets ofSIV and METH, as well as accessible biofluids. In combination with the in vitro systems in H. Gendelman'sProject ,1 and clinical samples in P. Ciborowski's Project 3, these nonhuman primate studies will form thenecessary bridge between the projects as well as allow us to directly assess, in the most accessible andvalid system, the target structures in the brain.Given the growing epidemic of METH use, and its relatively frequent abuse in the HIV infected population,this work is relevant to public health in the US. Knowledge about how METH is toxic to the brain in thesetting of HIV infection will be useful not only in discouraging METH use, but in obtaining disease-specificmarkers that can be used for diagnosis and guiding therapeutic interventions.
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