During the era of antiretroviral (ARV) therapy, the clinical syndrome of HIV associated dementia has evolved to a slower progression whereby clinical and radiological parameters lack the sensitivity for monitoring disease progression. This has posed unique challenges for conducing clinical trials with neuroprotective agents and for managing this patient population. The development of proteomics based biomarkers and surrogate markers are critical since they hold the promise of being sensitive to minor changes in brain function at a cellular level. Preliminary data from our group suggest that post translational modifications in proteins as a result of oxidative stress correlate with cognitive dysfunction. Recent advances in mass spectrometry (MS) have made it feasible to study large numbers of proteins simultaneously in biological fluids and to identify the proteins with relative ease. Taking advantage of these unique opportunities, the overarching theme of the proposed Pilot Proteomics Center for HIV-related Dementia and Drug Abuse is the discovery, identification and development of novel biomarkers for HIV-associated cognitive disorders and dementia in drug abusing patients. We have identified this as a high priority on the basis of our institutional strengths and continuing importance in clinical care. There is already a wealth of investigator-initiated HIV neuroscience research at Johns Hopkins University (JHU), especially focused on proteomics, pathogenesis, as well as significant expertise in clinical trial design. Despite this rich environment, currently there are no universally accepted, clinically accepted biomarkers available for HIV-associated cognitive disorders. Within the JHU Proteomics and HIV Neuroscience community, potential collaborations for biomarker development are currently limited by the lack of a strong central organizing structure, and specifically a facility to link different types of research, and to facilitate cross-disciplinary research. This Center will address these deficiencies. We propose three interactive projects, 1) Cerebrospinal Fluid (CSF) proteomic analysis will be performed on a well defined cohort of HIV infected drug abusers. A pilot study on the genetic markers that contribute to oxidative stress pathways will also be examined. 2) Similar proteomics analysis in CSF from SIV encephalitis model and 3) An in vitro human brain model of HIV infection and drug abuse.
The goal of this project is to develop highly sensitive biomarkers of cognitive dysfunction in HIV infected drug abusing populations. We will focus our efforts on the identification of proteins that are uniquely modified during these disease states. We hope that monitoring these biomarkers will help us conduct clinical trials in patients over shorter durations and with smaller numbers of patients. This will translate to better patient care and prevention of cognitive dysfunction in these patients.
|Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48|
|Tharakan, Ravi; Edwards, Nathan; Graham, David R M (2010) Data maximization by multipass analysis of protein mass spectra. Proteomics 10:1160-71|