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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-DSR-N (51))
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Sanford-Burnham Medical Research Institute
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Okamoto, Shu-ichi; Lipton, Stuart A (2015) S-Nitrosylation in neurogenesis and neuronal development. Biochim Biophys Acta 1850:1588-93
Zhu, Saiyong; Ambasudhan, Rajesh; Sun, Woong et al. (2014) Small molecules enable OCT4-mediated direct reprogramming into expandable human neural stem cells. Cell Res 24:126-9
Jeon, Gye Sun; Nakamura, Tomohiro; Lee, Jeong-Seon et al. (2014) Potential effect of S-nitrosylated protein disulfide isomerase on mutant SOD1 aggregation and neuronal cell death in amyotrophic lateral sclerosis. Mol Neurobiol 49:796-807
Chan, Shing Fai; Sances, Sam; Brill, Laurence M et al. (2014) ATM-dependent phosphorylation of MEF2D promotes neuronal survival after DNA damage. J Neurosci 34:4640-53
Choi, Min Sik; Nakamura, Tomohiro; Cho, Seung-Je et al. (2014) Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models. J Neurosci 34:15123-31
Okamoto, Shu-Ichi; Nakamura, Tomohiro; Cieplak, Piotr et al. (2014) S-nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death. Cell Rep 8:217-28
Molokanova, Elena; Akhtar, Mohd Waseem; Sanz-Blasco, Sara et al. (2014) Differential effects of synaptic and extrasynaptic NMDA receptors on A?-induced nitric oxide production in cerebrocortical neurons. J Neurosci 34:5023-8
Marco, Sonia; Giralt, Albert; Petrovic, Milos M et al. (2013) Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models. Nat Med 19:1030-8
Sunico, Carmen R; Nakamura, Tomohiro; Rockenstein, Edward et al. (2013) S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson's disease. Mol Neurodegener 8:29
Talantova, Maria; Sanz-Blasco, Sara; Zhang, Xiaofei et al. (2013) A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:E2518-27

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