The unifying theme of this revised P01 Grant renewal is a cellular and molecular approach to intellectual and developmental disabilities in an attempt to uncover processes contributing to neuronal synaptic damage, particularly in Down syndrome (DS). Three inter-related projects are planned. They all study overstimulation of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR), leading to synaptic damage and cognitive dysfunction in children. Here we show that oligomers of AP protein, as found in DS with or without Alzheimer's disease, can trigger excessive stimulation of extrasynaptic NMDARs, contributing to loss of thin dendritic spines, with resulting compromise of synaptic function and cognitive ability. This P01 Grant is credited with developing the first clinically-tolerated NMDAR antagonist, Memantine, which we showed is an uncompetitive, open-channel blocker with a relatively fast off-rate, accounting for its clinical tolerability. We then developed new, more effective drugs, called NitroMemantines, for the treatment of neonatal hypoxic- ischemic brain damage. NitroMemantines act on NMDAR channels (like Memantine) but also donate NO species to react at nitrosylation sites on the NMDAR to further downregulate excessive activity better than Memantine. Additionally, we plan to develop novel drugs based on structure-function relationships of the NR3 family of NMDAR subunits, which were discovered under the auspices of this PO1 grant. Project I will study the basis of NitroMemantine action and develop new NMDAR antagonists based on NR3 structure- function. Project II will test NitroMemantine vs. Memantine to prevent synaptic damage and cognitive deficits in DS using human fetal and IPS cell-based models in culture and the mouse Ts65Dn model in vivo. Project III will complement Project II by taking a genetic rather than a pharmacologic approach to downregulating excessive NMDAR activity or its downstream effects. Accordingly, Project III will test genetic models of altered NR3 genes or the downstream takusan family of genes for neuroprotection in similar in vitro and in vivo models of DS as in Project 11. The CORE supports administration, statistics, tissue culture, and crystallography/modeling of NMDAR subunits and functional sites, all critical to the proposed Projects.

Public Health Relevance

This grant aims to develop novel, clinically-tolerated NMDA receptor antagonists, called NitroMemantines, in addition to other novel molecules based on the structure of NRS subunits, which this Team of Investigators discovered, in order to prevent cognitive deficits seen in Down syndrome. To do this, we take two approaches, pharmacological and genetic, and use electrophysiological, histological, and behavioral analyses.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD029587-19
Application #
8634127
Study Section
Special Emphasis Panel (ZHD1-DSR-N (51))
Program Officer
Oster-Granite, Mary Lou
Project Start
1997-09-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$1,503,493
Indirect Cost
$732,471
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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