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Connecting the Nation's Researchers, Patients and Communities: Next Steps

Connecting the Nation's Researchers, Patients and Communities: Next Steps Biological and Environmental Research Advisory Committee Department of Energy September 1, 2009. Barbara Alving, M.D., M.A.C.P. Director National Center for Research Resources www.ncrr.nih.gov.

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Connecting the Nation's Researchers, Patients and Communities: Next Steps

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  1. Connecting the Nation's Researchers, Patients and Communities: Next Steps Biological and Environmental Research Advisory Committee Department of Energy September 1, 2009 Barbara Alving, M.D., M.A.C.P. Director National Center for Research Resources www.ncrr.nih.gov

  2. National Center for Research Resources Translating research from basic discovery to improved patient care animal model resources community engagement science education Pre-clinical Improved patient care Community technology & informatics advances research capacity & training Clinical clinical research support

  3. NCRR Div Clinical Research: Clinical and Translational Science Awards (will include 60 academic health centers working as a consortium and as a cooperative agreement with NIH) To ensure new discoveries lead to improved public health, clinical science must evolve to better: • Implement biomedical discoveries • Develop, test, and bring new prevention strategies into medical practice more rapidly • Catalyze change - lower barriers between disciplines • Encourage creative and innovative approaches. www.CTSAWeb.org

  4. Five CTSA Strategic Goals To enhance: National Clinical Research Capability and Efficiency Training and Career Development of Clinical and Translational Investigators Consortium-Wide Collaborations Health of Our Communities and the Nation T1 Translational Research

  5. NCRR Division of Biomedical Technology Translating discoveries into tools for biomedical research • Biomedical Technology Research Centers (BTRC) • Shared Instrumentation • High-End Instrumentation • Investigator-Initiated Research Grants (R01, R21) • Biomedical Informatics Research Network (BIRN) • Small Business Opportunities (SBIR/STTR) Advances in technology open new areas of inquiry Technology Discovery Biomedical discoveries create a need for new technologies

  6. Shared and High-End Instrumentation Program (S10): Overview • Unique and critical NIH mechanisms • Provide funding in cost-range from $100K to $2.0M • SIG Program (funding range $100k to $500K) • HEI Program (funding range $750k to $2.0M) • Equipment which is too costly to obtain with regular NIH research grants • Highly cost-effective mechanisms • Instruments placed in core facilities • Shared by an average of 8-10 grantees

  7. Biomedical Informatics Research Network (BIRN) A shared biomedical IT infrastructure • Collaboration between groups with different expertise and resources (technical, scientific, social and political) • Shared infrastructure to support collaboration (designed to be extensible to other biomedical communities) • Open access and dissemination of data and tools (i.e. Open Source) • Bringing transparent GRID Computing to Biomedical Research

  8. BTRCs: 52 Nationally Accessible Engines for Translational Research BTRCs Individual Investigators NIH Programs CTSA Consortium • Enabling technologies • Expertise • Computing Technology Discovery Each BTRC is accessible to NIH-supported investigators and programs from across the nation.

  9. Biomedical Technology Research Centers • Imaging • Technology • MRI • Image-guided therapy • PET • CAT • Ultrasound Informatics Resources • Genetics • Modeling of complex systems • Molecular dynamics • Visualization • Imaging informatics Optics & Laser Technology • Microscopy • Fluorescence spectroscopy • In Vivo diagnosis • 52 Unique Centers classified in 5 Broad Areas • Scope: from basic discovery to clinical research • Scale: from molecule to organism Technology for Structural Biology • Synchrotron x-ray technologies • Electron microscopy • Magnetic resonance Technology for Systems Biology • Mass spectrometry • Proteomics • Glycomics & glycotechnology • Flow cytometry

  10. Interagency Collaboration for Development of Biomedical Technology NCRR interacts with DOE through our Biomedical Technology Research Centers (BTRC) program: BTRC program BTRCs located at DOE National Laboratories Systems Biology BTRCs Structural Biology BTRCs 3 jointly supported with DOE/BER Technology for Structural Biology • Synchrotron x-ray technologies • Electron microscopy • Magnetic resonance Technology for Systems Biology • Mass spectrometry • Proteomics • Glycomics & glycotechnology • Flow cytometry

  11. NCRR Leverages Resources at DOE National Laboratories to support NIH research • NCRR Division of Biomedical Technology • Funds Biomedical Technology Research Centers (BTRC) to translate advances in physical sciences into tools for biomedical research • DOE National Labs • Facilitate R&D that is expensive and complex • Presents opportunities for NCRR to leverage unique expertise and infrastructure in the physical sciences • Personnel • Instrumentation development • Instrumentation access NCRR Enables $200M of NIH-funded research by supporting nine BTRCs for $20M at seven National labs through

  12. Systems Biology Biomedical Technology Research Centers at National Laboratories National Flow Cytometry Resource Los Alamos National Laboratory National Resource for Biomedical Accelerator Mass Spectrometry Lawrence Livermore National Laboratory Proteomics Research Resource for Integrative Biology Pacific Northwest National Laboratory Technology for Systems Biology • Mass spectrometry • Proteomics • Glycomics & glycotechnology • Flow cytometry

  13. National Flow Cytometry Resourceat Los Alamos National Laboratory (LANL) • Development of new instrumentation and applications • Access to unique LANL infrastructure • Access to scientists with unique technical and mathematical capabilities • Provides access to state-of-art flow cytometry instrumentation • Provides training for the biomedical research community New technology: flow cytometry based on sound waves Training: “build a cytometer” course

  14. A simple, low cost, compact data acquisition system for compact, portable flow cytometersNational Flow Cytometry Resource, LANL Developed a data system for use in low cost and/or portable instruments, based on a commercial electronics board. NFCR makes these systems available to collaborators Relatively low cost ($500) Technology licensed by Acoustic Cytometry Systems, which has since been acquired by Invitrogen

  15. National Resource for Biomedical Accelerator Mass Spectrometryat Lawrence Livermore National Laboratory (LLNL) Exquisitely sensitive technology for metabolic studies Allows safe microdosing with toxic or experimental molecules in humans 14C-AMS has allowed critical questions to be answered in human nutrition, metabolism, pharmacology, and comparative medicine. 1 Megavolt Biomedical AMS Instrument 10 Megavolt Instrument • LLNL Center for Accelerator • Mass Spectrometry (CAMS) • is the foundation for the BioAMS BTRC • Expertise • Engineering • Infrastructure

  16. 10 testicular cancer cells (sensitive to drug) amol 14C/mg of DNA Breast and bladder cancer cells (resistant to drug) 0 50 0 25 Time (h) Translating AMS: Identification of chemoresistance for personalized chemotherapy National Resource for Biomedical Accelerator Mass Spectrometry, LLNL • Highly toxic chemotherapy is often ineffective (response rate for non-small cell lung cancer <30%, bladder cancer 50%) • Identify chemoresistance by measuring chemotherapy-induced cell damage • Using ultrasensitive AMS, chemoresistance and the underlying mechanisms can be identified before patients receive toxic chemotherapy Oxaliplatin-induced DNA adducts in cell lines Example: 14C-labeled platinum derivatives, the most commonly used chemotherapeutic drugs.

  17. 1400 1400 m/z m/z 100 100 41 21 26 31 36 22 27 32 37 42 1400 m/z IMS Drift Time IMS Drift Time 100 24 29 34 39 44 Intensity IMS Drift Time IMS Drift Time 0 3 6 9 12 15 Time (minutes) Proteomics Research Resource Center for Integrative Biology at Pacific Northwest National Laboratory (PNNL) Next Generation Proteomics Platform: Prototype LC-IMS-MS • Ultra-sensitive & high throughput proteomics technologies and supporting informatics capabilities • Leverages a large base of DOE instrumentation, infra-structure, and EMSL DOE User Facility investments • Growing number of clinical/translational proteomics applications (e.g. partner with UW and OHSU CTSAs)

  18. “Spatial mapping of protein abundances in the mouse brain by voxelation integrated with high-throughput liquid chromatography-mass spectrometry.” V.A. Petyuk, W.-J. Qian, M.H. Chin, H. Wang, E.A. Livesay, M.E. Monroe, J.N. Adkins, N. Jaitly, D.J. Anderson, D.G. Camp II, D.J. Smith, & R.D. Smith. Genome Research 17, 328-336 (2007). 3-D mapping of proteins in mouse brain enabled by voxelation and quantitative proteomics Proteomics Research Resource Center for Integrative Biology, PNNL Collaboration with Prof. Desmond Smith; UCLA • Analysis of one voxelated mouse brain at 1 mm resolution requires proteome analysis of ~700 tissue samples • Quantitation and spatial distributions obtained for >1000 distinct proteins

  19. Proteomics analysis Proteomics Research Resource Center for Integrative Biology, PNNL Collaboration with the “Inflammation and Host Response to Injury” Glue Grant (NIGMS)Proteomics analysis: 100 trauma subjects, over 7 time points (12 hour intervals) Monocyte and T-cell Proteins • High throughput quantitative proteomics • Longitudinal analysis of T-cell and monocyte samples from severe trauma patients • Revealed 24 proteins predictive of bad outcomes (multiple organ failure) • Superior to microarray transcriptomic studies for same samples • Extending to larger patient population • Pathway analysis to establish biological context Patient classification based on 24 proteins observed in T-cells Good outcome Bad outcome

  20. Structural Biology Biomedical Technology Research Centers at National Laboratories BioCARS: A Synchrotron Structural Biology Resource U of Chicago, APS, Argonne National Laboratory Biophysics Collaborative Access Team Illinois Institute of Tech, APS, Argonne National Laboratory Undulator Resource for Structural Biology Cornell U, APS, Argonne National Laboratory Macromolecular Crystallography at the National Synchrotron Light Source Brookhaven National Laboratory, NSLS Synchrotron Radiation Structural Biology Resource Stanford, SSRL, SLAC National Accelerator Laboratory National Center for X-Ray Tomography UCSF, Lawrence Berkeley National Laboratory Technology for Structural Biology • Synchrotron x-ray technologies • Electron microscopy • Magnetic resonance

  21. Synchrotron BTRCs Leverage DOE Facilities Develop New TechnologiesProvide Access for Structural and Cellular Biology WA ME MT IIT, APS ND VT Tom Irving NY Cornell U., APS MN OR NH MA UCSF, LBNL Steve Ealick WI ID Carolyn Larabell SD MI CT WY RI PA IA Brookhaven NJ Stanford Univ NE IN NV Keith Hodgson Bob Sweet DE OH IL MD UT WV CO VA CA DC KS MO KY U. Chicago, APS NC TN Keith Moffat OK AR SC AZ NM AL MS GA LA TX FL • Over 40% of all research done at synchrotrons is in the life sciences

  22. Stanford Synchrotron Radiation Laboratoryat SLAC National Accelerator Laboratory • Cooperatively funded by NCRR and DOE/BER • Integrates 3 structural biology technology development areas to serve the needs of the biomedical and environmental science communities • Macromolecular crystallography • X-ray absorption spectroscopy • Small angle x-ray scattering • Services feature robotics and remote data collection

  23. 2006 Chemistry Nobel Prize - R. Kornberg DNA Transcription and Regulation • Research area of R. Kornberg; most of the synchrotron work was performed at SSRL and strongly enabled by the robotics • Transcription is the process by which DNA is “read” and converted into a message that directs protein synthesis with extremely high fidelity • Synchrotron-enabled studies have • provided molecular-level insight • into the function of this molecular • machine • This structural information now • serves to guide the development • of new antibiotics

  24. Parasite Nucleus Hemoglobin Maurer’s clefts Digestive vac. National Center for X-ray Tomographyat the Lawrence Berkeley National Laboratory Imaging Room Soft X-rays (517 eV) Malaria-infected RBC Microscope • New technology to obtain 3D views of • whole, hydrated cells in their native state at • better than 50 nm resolution • Bridges the mesoscale resolution “gap”, • The middle area between light (200 nm) and • electron microscopy (3 Ångstroms) • Can locate position of tagged molecules with respect to unstained cell structures

  25. Life Sciences Beamlines at NSLS-IIat Brookhaven National Laboratory • NCRR and BER jointly fund beamlines for Life Sciences (biomedical and biological) research at the existing National Synchrotron Light Source at Brookhaven National Laboratory • NSLS-II will replace NSLS, becoming operational in 2015 • NIH will construct new beamlines for life sciences that will benefit both NIH and DOE/BER Researchers • NCRR looks forward to continued cooperative funding of the life sciences programs at NSLS-II with DOE/BER NSLS 1984-2012 NSLS-II, 2015-

  26. NCRR and DOE work cooperatively to support Life Sciences Research • DOE • National Labs facilitate R&D that is expensive and complex • unique expertise and infrastructure in the physical sciences • NCRR Division of Biomedical Technology • translates advances in physical sciences into tools for biomedical research • DOE / NCRR Interaction • 9 BTRCs at 7 National Labs • Collaborations with BER to advance unique technologies for • biological and environmental research • Enable $200M of NIH-funded research

  27. American Recovery and Reinvestment Act (ARRA) Budget Components Other HHS (AHRQ) to also transfer ARRA appropriated $10 Billion (B) directly to NIH $8.2 B $1.0 B $0.5 B $0.3 B $0.4 B Extramural Scientific Research (All ICs, OD) Extramural Construction (NCRR) Intramural Repair & Improvement & Constr. (B&F) SIG & Other Cap Equip (NCRR) Comparative Effectiveness Research (OD) Financial & Employment Reporting

  28. NCRR Funding through ARRA • $1.0 Billion for construction, repair and renovation • RFA for Extramural Research Facilities Improvement Program (C06) • RFA for Core Facility Renovation, Repair and Improvement (G20) • $300 Million for shared instrumentation and other capital research equipment • RFA for Shared Instrumentation Grant (SIG) • RFA for High End Instrumentation (HEI) • $310 Million for scientific research • Supplements to existing resource programs in NCRR

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