Mass spectrometry is based on fragmenting biological molecules into smaller pieces, and using the fragment masses as a fingerprint for identifying and quantifying bio-molecules. It is the dominant technology for studying active molecules in healthy and diseased tissue, and identifying protein targets and natural products for novel therapeutics. When the initial proposal Center for Computational Mass Spectrometry (CCMS) was submitted in 2007, the lack of adequate computational tools for analyzing mass spectrometry data was the the key bottleneck. With great success in enabling applications of new experimental techniques such as FTMS, ETD, HCD, top-down mass spectrometry, and many others, the mandate of CCMS continues to be the development of next generation computational technologies and to apply them to open experimental. In this proposal, we will capitalize on our recent results in diverse subfields of computational proteomics and will further branch into previously unexplored MS applications. We will focus specifically on bridging proteomics and genomics technologies using 6 technology research and development platforms. Specifically, we will (a) apply proteogenomics approach for the discovery of abberant cancer genes and analyzing antibody repertoires; (b) sequence natural antibiotics; (c) collate spectral data through spectral archives and networks; (d) develop universal tools for peptide identification; (e) develop tools for top-down proteomics; and, (f) analyzing multiplexed spectra. The technology platforms are driven by a multitude of col- laborative biomedical studies where the use of CCMS developed tools is essential for their success. These studies include (a) unraveling the combinatorial histone code in human diseases; (b) a proteogenomics approach to studies of oral microbiome and polybacterial infections; (c) detecting inter-species chemical in- teractions; (d) developing a systems approach towards the therapeutic modulation of the acetylome ; (e) developing tools for monoclonal and polyclonal antibody sequencing; (f) development of breast cancer vac- cines; (g) clinical cancer proteogenomics; (h) discovery of lantibiotics; (i) discovering proteomic biomarkers for drug toxicity in cancer patients; and, (j) identifying protein-protein interactions and post-translational mod- ifications in cataractous lens. These projects require three-way collaborative efforts on a wide range of topics involving biomedical scientists, mass spectrometrists, and computational scientists from various institutions. CCMS will also train students and practicing scientists from all over the world in computational proteomics, and educate the proteomics community about modern computational mass spectrometry to encourage its wide adoption.

Public Health Relevance

The proposal involves the development of computational technologies for analyzing mass spectrometry data that will directly impact biomedical projects, including therapuetic antibody sequencing using a combina- tion of DNA sequencing and proteomics, analyzing antibody repertoires to analyze complex immunological responses, decoding the histone code and histone isoforms that are relevant to cancer, finding aberrant proteins that represent hallmarks of cancer abnormalities, and many others.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM103484-09
Application #
9303398
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Edmonds, Charles G
Project Start
2008-09-20
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Caraballo-Rodríguez, Andrés M; Dorrestein, Pieter C; Pupo, Monica T (2017) Molecular inter-kingdom interactions of endophytes isolated from Lychnophora ericoides. Sci Rep 7:5373
Trevisan-Silva, Dilza; Bednaski, Aline V; Fischer, Juliana S G et al. (2017) A multi-protease, multi-dissociation, bottom-up-to-top-down proteomic view of the Loxosceles intermedia venom. Sci Data 4:170090
Hartmann, Aaron C; Petras, Daniel; Quinn, Robert A et al. (2017) Meta-mass shift chemical profiling of metabolomes from coral reefs. Proc Natl Acad Sci U S A 114:11685-11690
Guthals, Adrian; Gan, Yutian; Murray, Laura et al. (2017) De Novo MS/MS Sequencing of Native Human Antibodies. J Proteome Res 16:45-54
Cha, Seong Won; Bonissone, Stefano; Na, Seungjin et al. (2017) The Antibody Repertoire of Colorectal Cancer. Mol Cell Proteomics 16:2111-2124
Scheubert, Kerstin; Hufsky, Franziska; Petras, Daniel et al. (2017) Significance estimation for large scale metabolomics annotations by spectral matching. Nat Commun 8:1494
Shlemov, Alexander; Bankevich, Sergey; Bzikadze, Andrey et al. (2017) Reconstructing Antibody Repertoires from Error-Prone Immunosequencing Reads. J Immunol 199:3369-3380
Edlund, Anna; Garg, Neha; Mohimani, Hosein et al. (2017) Metabolic Fingerprints from the Human Oral Microbiome Reveal a Vast Knowledge Gap of Secreted Small Peptidic Molecules. mSystems 2:
Mohimani, Hosein; Gurevich, Alexey; Mikheenko, Alla et al. (2017) Dereplication of peptidic natural products through database search of mass spectra. Nat Chem Biol 13:30-37
Deutsch, Eric W; Csordas, Attila; Sun, Zhi et al. (2017) The ProteomeXchange consortium in 2017: supporting the cultural change in proteomics public data deposition. Nucleic Acids Res 45:D1100-D1106

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