Project I - Zhang &Chen Program Director/Principal Investigator (Last, First, Middle): Lipton, Stuart A. PROJECT SUMMARY (See instructions): The N-methyl-D-aspartate subtype of gluatmate receptor (NMDAR) is essential for normal function of the central nervous system (CNS). However, excessive activation of NMDARs, particulariy of extrasynaptic as opposed to synaptic receptors, mediates, at least in part, neuronal or synaptic damage in many neurological disorders, such as hypoxic-ischemic brain injury and, as recently suggested, in Down syndrome. Blockade of excessive NMDAR activity must be achieved without interference with its normal brain function. We have taken two approaches for clinically-tolerated pharmacological and genetic intervention on NMDARs. One approach is to use Memantine but also NO species to further down regulate the NMDAR by S-nitrosylation. The structural determinants on NMDARs for the action of Memantine and NO-like species will be characterized further under the auspices of this grant. Another approach is to utilize the inhibitory effect of a novel family of NMDAR subunits, composed of NRSA and NRSB, to downregulate NMDARs by affecting channel permeability, in a sense mimicking the effect of the NMDAR antagonist drugs that are also being developed here. We will study the role of the MS domain of NRS subunits that downregulate activity of NMDARs and also design NRS ligand-binding domain (LBD)-based screening assays to discover new compounds that modulate NRS-containing receptors. These agents will be useful for characterizing NRS-containing receptors, and possibly for neuroprotection. Accordingly, the Specific Aims of this proposal are as follows: 1) To study the effect of S-nitrosylation/redox modulation of the loose linker region between the amino-terminal domain (ATD) and the LBD of NMDARs by electrophysiology;2) To develop LBD-derived screening assays to screen for ligands selective for the NRS subunit of the NMDAR. These ligands will be further characterized and refined by secondary assays, chemical modification, and co-crystallization;3) To study the inhibitory effect of peptides derived from the out vestibule (MS) region of NRS subunits on NMDAR permeability.

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 the NRS subunit, which this Team of Investigators discovered, in order to prevent cognitive deficits seen in Down syndrome. We take two approaches, pharmacological and genetic, for safe inhibition of NMDARs to treat pathological conditions without interference with normal function.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD029587-18
Application #
8431749
Study Section
Special Emphasis Panel (ZHD1-DSR-N)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
18
Fiscal Year
2013
Total Cost
$418,604
Indirect Cost
$203,179
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mann, Aman P; Scodeller, Pablo; Hussain, Sazid et al. (2018) Publisher Correction: Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer's disease. Nat Commun 9:1070
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
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
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 (2017) 'SNO'-Storms Compromise Protein Activity and Mitochondrial Metabolism in Neurodegenerative Disorders. Trends Endocrinol Metab 28:879-892
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 (2016) Protein S-Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases. Trends Pharmacol Sci 37:73-84
Macrez, Richard; Stys, Peter K; Vivien, Denis et al. (2016) Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities. Lancet Neurol 15:1089-102

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