CORE B - Zhang &Lipton Program Director/Principal Investigator (Last, First, Middle). Llpton, Stuart A. PROJECT SUMMARY (See instructions): The Neuroscience Research CORE (CORE B) is divided into a Tissue Culture/Animal SubCore and a Crystallography/Molecular Modeling SubCore. The objective of the Tissue Culture/Animal SubCore is to provide each ofthe projects with assistance in mouse breeding/genotyping, cell culture and related experiments, and to provide large items of equipment for common use. The cost-effectiveness of the Core is achieved by having a core serve all 3 projects in order to eliminate duplication of effort. For example, in the Neuroscience Core, skilled technicians produce a variety of high quality neuronal cultures derived from primary tissues or stem cells, particulariy neurons from valuable fetal brain and iPSCs from human Down syndrome (DS), which will allow us to study the effect of NMDA receptors (NMDARs) and related molecules in DS. The objective of the Crystallography/Molecular Modeling SubCore is to use two types of structural approaches, crystallography and molecular modeling, to assist us in elucidating the mechanism of NMDAR activation and, consequently, in designing improved drugs that can modulate NMDARs for neuroprotection. Crystallography will provide structural information on the NMDAR at atomic resolution and molecular modeling will provide a framework to predict and interpret perturbations of receptor function by mutations or drugs when direct experimental data (i.e., crystal structures) are as yet unavailable. The multi-disciplinary approach provided by this Core is critical for solving the complex problem of structure-function analysis of NMDARs in this Program Prbject and how this information can be harnessed for protecting synaptic integrity in DS. Integrated leadership in the Core is achieved by Dr. Zhang attending to the day-to-day activities ofthe Core, for which he has 14 years of experience, while Dr. Lipton oversees the overall mission, interactions, and relevance of the Core to each project. The Scientific Core enables the work of all 3 projects in this Program Project Grant, and draws upon the tissue culture, animal breeding, and stem cell knowledge in Dr. Lipton's laboratory as well as the crystallography and modeling expertise of Drs. Zhang, Jin and Godzik, in conjunction with the considerable molecular and genetic experience of Dr. Nakanishi.

Public Health Relevance

The Scientific Core will allow us to pursue model systems in which we can study the influence of NMDA receptors and related molecules in protecting nerve cells from damage in Down syndrome (DS). The Core serves the 3 projects in this Program Project that have a unified goal to find new treatments for cognitive deficits in DS.

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 #
8431754
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
$218,116
Indirect Cost
$106,926
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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