The unifying theme of this competing renewal program project is a cellular and molecular approach to developmental neurology in an attempt to uncover processes contributing to neonatal brain injury and mental retardation. The continuation of three interrelated projects is planned. They all concern the influence of overstimulation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) leading to neuronal damage during hypoxic-ischemic brain injury and other insults to the brain. Hypoxic-ischemic insults are known to result in mental retardation and developmental delay. This group of program investigators has shown that at least part of this damage to the nervous system appears to be mediated by excessive NMDAR activation that is not adequately treated by currently available therapeutic regimens. This program project developed the first clinically tolerated NMDAR antagonist, memantine, which the investigators showed is an uncompetitive, open-channel blocker. Here by studying NMDAR structure/function, they will develop improved derivatives of memantine. These drugs are known as the NO-memantines, and are more effective neuroprotectants than memantine because they target, via memantine, NO species to a nitrosylation site on NMDARs to further downregulate excessive activity. Additionally, the investigators have cloned and are studying a new family of NMDAR subunits (the NR3 family comprised of NR3A and NR3B) that are also neuroprotective during neonatal development, in some sense mimicking the effect of the drugs. They are studying NR3 using a range of multidisciplinary approaches with (i) recombinant receptors (using site-directed mutagenesis, electrophysiology, and crystallography of subunit proteins in Project I), (ii) cell biology of primary neurons (patch-clamp and neurodegenerative studies in Project II), and (iii) systems biology (electrophysiology and molecule expression of gene-targeted mice in Project III). In addition, novel NO-memantines will be tested in animal models of hypoxic-ischemic brain injury in Project II. The core supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites.
Showing the most recent 10 out of 175 publications
