CHEMICAL LIBRARY SCREENING CORE 1. MAIN OBJECTIVES AND DIRECTIONS The mission of the Chemical Library Screening (CLS) Facility Core is to provide new chemical tools and potential drug develop to Neuroscience investigators. The utility of small molecule screening for solving problems in biology is illustrated by a number of recent reports in the literature (see citations below). It is also anticipated that this route of study will provide assay and chemical inputs into the pipeline for the development of new lead molecules for the treatment of neurological disorders. Since high-throughput screening is not widely available at academic institutions, this facility will provide a new and unique approach toward characterizing proteins and signaling pathways involved in many aspects of neural development and neurologic disease. This Core will be located at the Burnham Institute for Medical Research (BIMR) and represents an expansion of an existing Core that was developed by BIMR's Cancer Center, but is not available to neuroscientists at this time. BIMR's contribution to this grant is represented by the institutional purchase of equipment, including the robotic screening facility, high-throughput microscopes, and chemical libraries, valued at well over $2 million. The proposed NIH Blueprint Neuroscience Core Center Grant will facilitate and encourage use of this Chemical Screening Core by neuroscientists on the La Jolla Torrey Pines Mesa at BIMR, The Salk Institute, The Scripps Research Institute (TSRI), and the University of California, San Diego (UCSD). The Core facility will offer chemical libraries, including an integrated robotic line with an automated incubator, plate hotel and tip loader, for biochemical assays with readouts including FRET, fluorescence polarization, and luminescence. Also offered is a complete high content screening line that includes robotics for liquid and plate handling, automated incubator, plate hotel in a clean-room environment for cell-based assays. Image-acquisition capabilities include Beckman Coulter and GE automated microscopes with robotic plate feeding. Sophisticated software packages are used for automated tracking of plates and compounds, cheminformatics, and image analysis. In general, two kinds of screens are performed with the following nomenclature: (i) HTS is high throughput screening, typically used for biochemical screens or plate-reader screens of cell-based assays;(ii) HCS is high content screening, used for image-based screens of cell assays, i.e. type of assays that use image analysis of cells. Expert assistance is available for all aspects of biochemical and cell-based screens, including automation engineering, medicinal chemistry, image acquisition, algorithm engineering and analysis. The CLS facility is located at BIMR within the San Diego Chemical Genomics Center (SDCGC), which also operates as one of the 9 NIH funded extramural centers of the Multiple Library Screening Center Network. The center is directed by Dr. Mark Mercola and managed by Dr. Steve Vasile. Dr. Mercola also directs Assay Development and Assay Implementation units of the SDCGC. Currently, the CLS facility operates as a charge-back basis to support members of the BIMR Cancer Center under the auspices of the BIMR Cancer Center Support Grant (CCSG). Because of heavy demand, it has offered only very limited and occasional service to members of the Cancer research community not at BIMR, and virtually no access to neuroscientists. The primary goal of this application is to provide salary support for personnel within CLS to support and facilitate interdisciplinary, collaborative research projects of neuroscience investigators on the La Jolla Torrey Pines Mesa.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Center Core Grants (P30)
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Special Emphasis Panel (ZNS1)
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Singec, Ilyas; Crain, Andrew M; Hou, Junjie et al. (2016) Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling. Stem Cell Reports 7:527-542
Kim, Changyoun; Lv, Guohua; Lee, Jun Sung et al. (2016) Exposure to bacterial endotoxin generates a distinct strain of ?-synuclein fibril. Sci Rep 6:30891
Valera, Elvira; Masliah, Eliezer (2016) Combination therapies: The next logical Step for the treatment of synucleinopathies? Mov Disord 31:225-34
Kratter, Ian H; Zahed, Hengameh; Lau, Alice et al. (2016) Serine 421 regulates mutant huntingtin toxicity and clearance in mice. J Clin Invest 126:3585-97
Kim, Changyoun; Lee, He-Jin; Masliah, Eliezer et al. (2016) Non-cell-autonomous Neurotoxicity of ?-synuclein Through Microglial Toll-like Receptor 2. Exp Neurobiol 25:113-9
Mandler, Markus; Valera, Elvira; Rockenstein, Edward et al. (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10:10
Tang, Bin; Wang, Tingting; Wan, Huida et al. (2015) Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome. Proc Natl Acad Sci U S A 112:E4697-706
Rockenstein, Edward; Overk, Cassia R; Ubhi, Kiren et al. (2015) A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies. PLoS One 10:e0121570
Hoefer, Melanie M; Sanchez, Ana B; Maung, Ricky et al. (2015) Combination of methamphetamine and HIV-1 gp120 causes distinct long-term alterations of behavior, gene expression, and injury in the central nervous system. Exp Neurol 263:221-34
Valera, Elvira; Mante, Michael; Anderson, Scott et al. (2015) Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson's disease. J Neuroinflammation 12:93

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