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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sanford-Burnham Medical Research Institute
La Jolla
United States
Zip Code
Tu, Shichun; Akhtar, Mohd Waseem; Escorihuela, Rosa Maria et al. (2017) NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism. Nat Commun 8:1488
Chen, Shanyan; Cui, Jiankun; Jiang, Tao et al. (2017) Gelatinase activity imaged by activatable cell-penetrating peptides in cell-based and in vivo models of stroke. J Cereb Blood Flow Metab 37:188-200
Nagar, Saumya; Trudler, Dorit; McKercher, Scott R et al. (2017) Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency. Invest Ophthalmol Vis Sci 58:3741-3749
Nakamura, Tomohiro; Lipton, Stuart A (2017) 'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders. Trends Endocrinol Metab 28:879-892
Nagar, Saumya; Noveral, Sarah M; Trudler, Dorit et al. (2017) MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress. Proc Natl Acad Sci U S A 114:E4048-E4056
Mann, Aman P; Scodeller, Pablo; Hussain, Sazid et al. (2017) Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. Nat Commun 8:1403
Satoh, Takumi; Lipton, Stuart (2017) Recent advances in understanding NRF2 as a druggable target: development of pro-electrophilic and non-covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Res 6:2138
Nakamura, Tomohiro; Lipton, Stuart A (2016) Nitrosative Stress in the Nervous System: Guidelines for Designing Experimental Strategies to Study Protein S-Nitrosylation. Neurochem Res 41:510-4
Nakamura, Tomohiro; Lipton, Stuart A (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Lipton, Stuart A; Rezaie, Tayebeh; Nutter, Anthony et al. (2016) Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer's disease models. Cell Death Dis 7:e2499

Showing the most recent 10 out of 173 publications