This Resource develops and uses Multi-isotope Imaging Mass Spectrometry (MIMS), the combination of a novel type of secondary ion mass spectrometer with tracer methods and intensive quantitative image analysis. MIMS provides high mass separation (M/AM >10,000) at high secondary ion transmission, high spatial resolution (35 nm) and has the unique capability of simultaneously recording several atomic mass images. Of the utmost importance, MIMS makes it possible for the first time, at the intracellular level, to simultaneously image the distribution and measure the accumulation of molecules labeled with any isotopes, in particular with stable isotopes, for example 15N. Thus, MIMS allows one to study the localization, the accumulation and the turnover of proteins, fatty acids, sugars and foreign molecules in cellular micro domains;the expression and distribution of DNA and RNA;the migration of donor cells to receiver niches, the nesting of stem cell and the intracellular localization of drugs. Finally, the use of stable isotopes opens a world of labeling possibilities that should revive and expand the use of tracers in humans. The Resource collaborates with researchers in cell biology, pathology, biochemistry, immunology, transplantation, pharmacology, stem cell research, microbiology and virology. Development of an iodine negative primary ion source will open subcellular isotope ratio imaging of secondary positive ions, in particular the experimental use of the multiple stable isotopes of calcium to dissect the function of this essential and ubiquitous intracellular agent, and the quantitative imaging of metallo-enzymes. Study of secondary ion formation will guide labeling schemes. Development of automation will allow us to perform complex analyzes 24/7, decomposing a cell from top to bottom in a succession of hundreds of quantitative atomic mass images, each obtained from the sputtering of a few atomic layers. Powerful software will allow us to rapidly extract and reduce quantitative information from reams of data and in a 3D space. Development of methods for long term labeling of cellular DNA will directly benefit immunology, transplantation, stem cell and cancer research. We will train users by organizing yearly workshop on the theory and practice of MIMS and a workshop on the use of the MIMS data reduction software. We will continue to accumulate on the Resource website information spanning all our procedures, results and happenings. We will make of our Web Site a centralized repository for ourselves and the community of users. This Resource is developing multi-isotope imaging mass spectrometry (MIMS), a new technology that makes it possible to image and quantify molecules within individual mammalian or bacterial cells. Called 'an imaging revolution'as quoted by J. Weitzman (2006, J. Biol. 5:16), MIMS will help solving intractable problems in all fields of biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Biotechnology Resource Grants (P41)
Project #
5P41EB001974-13
Application #
8322636
Study Section
Special Emphasis Panel (ZRG1-BCMB-N (40))
Program Officer
Liu, Christina
Project Start
2003-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$1,114,866
Indirect Cost
$477,800
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Kojima, Toru; Yamada, Hiromi; Isobe, Mitsuru et al. (2014) Compositional changes of human hair melanin resulting from bleach treatment investigated by nanoscale secondary ion mass spectrometry. Skin Res Technol 20:416-21
Jones, David L; Clode, Peta L; Kilburn, Matt R et al. (2013) Competition between plant and bacterial cells at the microscale regulates the dynamics of nitrogen acquisition in wheat (Triticum aestivum). New Phytol 200:796-807
Senyo, Samuel E; Steinhauser, Matthew L; Pizzimenti, Christie L et al. (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493:433-6
Steinhauser, Matthew L; Bailey, Andrew P; Senyo, Samuel E et al. (2012) Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism. Nature 481:516-9
Zhang, Duan-Sun; Piazza, Valeria; Perrin, Benjamin J et al. (2012) Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair-cell stereocilia. Nature 481:520-4
Gormanns, Philipp; Reckow, Stefan; Poczatek, J Collin et al. (2012) Segmentation of multi-isotope imaging mass spectrometry data for semi-automatic detection of regions of interest. PLoS One 7:e30576
Lechene, Claude P; Luyten, Yvette; McMahon, Gregory et al. (2007) Quantitative imaging of nitrogen fixation by individual bacteria within animal cells. Science 317:1563-6
Lechene, Claude; Hillion, Francois; McMahon, Greg et al. (2006) High-resolution quantitative imaging of mammalian and bacterial cells using stable isotope mass spectrometry. J Biol 5:20
McMahon, G; Saint-Cyr, H Francois; Lechene, C et al. (2006) CN- secondary ions form by recombination as demonstrated using multi-isotope mass spectrometry of 13C- and 15N-labeled polyglycine. J Am Soc Mass Spectrom 17:1181-7