The goal of the proposed study is to explore the biological and biophysical properties of living cells that are decorated with unnatural fluorinated carbohydrates on their surfaces. It has been found that this cell-surface modification reduces cell adhesion, and therefore may provide a means to treat human disease processes that are mediated by cell adhesion such as tumor metastasis and inflammation. Part of this project is designed to determine the effect of cell-surface fluorine modification on biological functions related to cellular adhesion. The ability of fluorinated sialic acids to reduce the rate or extent of tumor metastasis will be studied by bioluminescent imaging in a murine model. The attachment of fluorinated molecules to the cell surface is accomplished by incubating the cells with chemically synthesized fluorinated sialic acid analogues that are taken up and processed into fluorinated glycoproteins and glycolipids expressed on the cell glycocalyx. Part of this project is to determine what the structural requirements are for a fluorinated sialic acid analogue to be expressed on the cell surface. Also, the distribution and nature of modified molecules on the cell surface will be determined by secondary ion mass spectrometry, by colorimetric assay of selectively cleaved cell-surface molecules, and by a chemical genetics approach. Since fluorinated molecules are virtually absent in unmodified cells, the incorporation of fluorine atoms provides an opportunity for low-background imaging by non-invasive techniques. Tumor bearing mice treated with fluorinated sialic acids will be imaged by 19F MRI. Since many tumor cells are hypersialylated, this technique may be useful for locating tumors before they are visible by other means.
The Specific Aims for this study are to: (1) determine the scope of fluorinated sialic acid analogues tolerated for expression on cultured cells;(2) evaluate the static adhesion characteristics of cells expressing fluorinated sialic acids and study the mechanism of altered adhesion;(3) characterize the surfaces of cells expressing fluorinated carbohydrates;(4) evaluate the effect of cell-surface fluorination on tumor metastasis in mice;and (5) evaluate 19F MRI of tumor-containing mice expressing fluorinated carbohydrates.
The proposed study is relevant to cancer therapy and potentially to inflammatory disease because it explores a new strategy for reducing cell adhesion. The study is also relevant for cancer diagnosis because it may provide a way to image tumors by MRI.
| Yüksel, Deniz; Bianco, Piero R; Kumar, Krishna (2016) De novo design of protein mimics of B-DNA. Mol Biosyst 12:169-77 |
| Zamora, Cristina Y; Ryan, Matthew J; d'Alarcao, Marc et al. (2015) Sialidases as regulators of bioengineered cellular surfaces. Glycobiology 25:784-91 |
| Akçay, Gizem; Ramphal, John Y; d'Alarcao, Marc et al. (2015) Total synthesis of trifluorobutyryl-modified, globally protected sialyl Lewis x by a convergent [2+2] approach. Tetrahedron Lett 56:109-114 |
| Doyle, Jamie R; Krishnaji, Subrahmanian T; Zhu, Guangli et al. (2014) Development of a membrane-anchored chemerin receptor agonist as a novel modulator of allergic airway inflammation and neuropathic pain. J Biol Chem 289:13385-96 |
| Chu, An-Hsiang Adam; Minciunescu, Andrei; Montanari, Vittorio et al. (2014) An air- and water-stable iodonium salt promoter for facile thioglycoside activation. Org Lett 16:1780-2 |
| Yu, Jian-Xin; Hallac, Rami R; Chiguru, Srinivas et al. (2013) New frontiers and developing applications in 19F NMR. Prog Nucl Magn Reson Spectrosc 70:25-49 |
| Zamora, Cristina Y; d'Alarcao, Marc; Kumar, Krishna (2013) Fluorogenic sialic acid glycosides for quantification of sialidase activity upon unnatural substrates. Bioorg Med Chem Lett 23:3406-10 |
| Lozano, Mónica M; Liu, Zhao; Sunnick, Eva et al. (2013) Colocalization of the ganglioside G(M1) and cholesterol detected by secondary ion mass spectrometry. J Am Chem Soc 135:5620-30 |
| Lorenz, Barbel; Alvarez de Cienfuegos, Luis; Oelkers, Marieelen et al. (2012) Model system for cell adhesion mediated by weak carbohydrate-carbohydrate interactions. J Am Chem Soc 134:3326-9 |
| Dafik, Laila; d'Alarcao, Marc; Kumar, Krishna (2010) Modulation of cellular adhesion by glycoengineering. J Med Chem 53:4277-84 |
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