The unifying theme of the revised, competing renewal of this Program Project is a cellular and molecular approach to developmental neurology in an attempt to uncover processes leading to neonatal brain injury and mental retardation. Four inter-related projects are planned. They all concern the influence of overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and related signaling pathways to neuronal damage during hypoxic-ischemic brain injury and AIDS. Hypoxic -ischemic insults are known to result in mental retardation and developmental delay. Only recently, however, has it become apparent that AIDS is associated with an approximately 50% incidence in delayed milestones and frank cognitive decline in children infected with HIV-1. This Program Project Group of Investigators and others have shown that at least part of this damage to the nervous system appears to be mediated by excessive NMDA receptor activation that is not adequately treated by currently available therapeutic regimens. This grant plans to study the underlying molecular mechanisms that can be used to down regulated NMDA receptor activity in aq clinically tolerant manner using a combination of techniques ranging from molecular biology and gene-targeting to patch-clamp recording. Two types of clinically tolerated NMDA antagonists are being developed: (1) open- channel blockers of the memantine class of compounds, and (2) nitric oxide (NO) related species (using nitroglycerin). Additional novel agents include a combinatorial drug, nitro-memantine, which targets NO species to NMDARs via the open-channel blocker. In projects, these novel, clinically-tolerated NMDA antagonists will be tested in animal models of hypoxic-ischemic and HIV-related brain injury. These projects will also explore signaling pathways downstream to NMDAR activity which mediate neuronal necrosis or apoptosis and involve nitric oxide and caspases. Rodent models consisting of transgenic and knockout mice will be used. Project has cloned, characterized and generated mice deficient in a new NMDAR subunit NR3A. The CORE supplies support for statistics, tissue culture, and magnetic resonance imaging/spectroscopy (MRI/MRS). An important feature of this Program Project is its multi-disciplinary approach using molecular biology, electrophysiology and imaging techniques both in vitro and in vivo. The team has a proven track record of hypothesis testing to help elucidate the pathogenesis of hypoxic-ischemic and AIDS-related injury in the brain, and then of using this knowledge for drug development, leading to human clinical studies.
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