THERAPEUTIC CORE PROJECT SUMMARY (See instructions): HIV-associated neurocognitive disorders (HAND) remain very prevalent, even among HIV-infected individuals who have been treated with highly active antiretroviral therapy. Thus, there is an unmet medical need to develop adjunctive therapies to treat HAND. Our previous studies in the Therapeutics Development core of the JHU NIMH Center for Novel Therapeutics have demonstrated that neuroprotective and/or neuroregenerative small molecule regimens protect vulnerable hippocampal and cortical neurons from oxidative stress and HIV viral proteins in vitro and in vivo, and therefore, may provide such a treatment for HAND. The continuing goal for the Therapeutics Core is to facilitate new adjunctive therapeutics development for the treatment of HIV-associated cognitive disorders. The therapeutics core will utilize techniques in neurobiology, medicinal chemistry, biopharmaceutics profiling and pharmacokinetic analysis as a combinatorial approach to identify and develop these therapies. Specifically, this Core will serve the following functions and has the following objectives: a)To use focused medium throughput screening, using in vitro models to identify novel compounds useful for treatment of HIV-associated cognitive dysfunction with the over-arching theme of reducing the sustained CNS inflammation that we believe underlies the development of HAND; b) to evaluate potential neuroprotective and neuroregenerative compounds in vivo; and c) To facilitate preclinical development of potential neuroprotective/neuroregenerative therapeutic agents, identified internally and by external investigators.

RELEVANCE (See instructions): HIV/AIDS is a major threat to global health and urban America, and HIV-associated-neurocognitive dysfunction remains prevalent even in HAART-treated people. Our research suggests that one of the drivers for this is sustained inflammation within the brain. Our Center has helped to coordinate and catalyze scientific and clinical resources at JHU to generate novel approaches to therapy.