The broad objective of this project is to apply a technique developed in our lab termed metabolic oligosaccharide engineering to in vivo imaging of global changes in the glycome associated with embryonic development and cancer. The "glycome" is the totality of glycans that cells produce under specified conditions of time, space and environment. Changes in the glycome's composition and distribution are associated with embryogenesis and cancer progression. We seek to develop chemical tools for imaging the dynamic cell-surface glycome in living organisms. We plan to pursue five specific aims that further expand the scope of the glycan imaging technology and apply our methods to new avenues of biological investigation.
Aim 1 builds directly from our ongoing work in zebrafish imaging, with a shift in focus to disease models in this organism.
Aim 2 seeks to expand the glycan imaging technique to bacterial systems, with an eye for monitoring changes in outer membrane glycolipids and capsular polysaccharides that might correlate with pathogenesis.
Aim 3 focuses on the , development of probes for imaging glycans in mouse tumor models, building from our earlier work in this model organism.
Aim 4 seeks to build the bioorthogonal reaction compendium with second-generation quadricyclane ligation chemistries as well as new reactions based on phosphinoboranes.

Public Health Relevance

The goal of this project is to develop tools from the field of chemistry that can help researchers and. physicians monitor the changes in cell-surface glycans inside the body using imaging techniques. These chemical tools could be useful for cancer detection and diagnosis.

National Institute of Health (NIH)
Method to Extend Research in Time (MERIT) Award (R37)
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Marino, Pamela
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University of California Berkeley
Schools of Arts and Sciences
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Shieh, Peyton; Siegrist, M Sloan; Cullen, Andrew J et al. (2014) Imaging bacterial peptidoglycan with near-infrared fluorogenic azide probes. Proc Natl Acad Sci U S A 111:5456-61
Sletten, Ellen M; de Almeida, Gabriela; Bertozzi, Carolyn R (2014) A homologation approach to the synthesis of difluorinated cycloalkynes. Org Lett 16:1634-7
Beahm, Brendan J; Dehnert, Karen W; Derr, Nicolas L et al. (2014) A visualizable chain-terminating inhibitor of glycosaminoglycan biosynthesis in developing zebrafish. Angew Chem Int Ed Engl 53:3347-52
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Van de Bittner, Genevieve C; Bertozzi, Carolyn R; Chang, Christopher J (2013) Strategy for dual-analyte luciferin imaging: in vivo bioluminescence detection of hydrogen peroxide and caspase activity in a murine model of acute inflammation. J Am Chem Soc 135:1783-95
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Sletten, Ellen M; Bertozzi, Carolyn R (2011) From mechanism to mouse: a tale of two bioorthogonal reactions. Acc Chem Res 44:666-76
Jewett, John C; Bertozzi, Carolyn R (2011) Synthesis of a fluorogenic cyclooctyne activated by Cu-free click chemistry. Org Lett 13:5937-9

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