Fluorinated Cell Surfaces to Modulate Biological Function

氟化细胞表面调节生物功能

• 批准号: 8071987
• 负责人: KRISHNA KUMAR
• 金额: $ 43.83万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071987
• 关键词: Adhesions; Biological; Biological Assay; Biological Process; Carbohydrates; Cell Adhesion; Cell physiology; Cell surface; Cells; Characteristics; Cleaved cell; Cultured Cells; Disease; Fluorine; Glycocalyx; Glycolipids; Glycoproteins; Goals; Health; Image; Imaging Techniques; In Vitro; Incubated; Inflammation; Inflammatory; Interest Group; Life; Magnetic Resonance Imaging; Mediating; Modeling; Modification; Mus; Nature; Neoplasm Metastasis; Process; Property; Reaction; Sialic Acids; Spectrometry, Mass, Secondary Ion; Surface; Techniques; analog; cancer diagnosis; cancer therapy; chemical genetics; design; human disease; neoplastic cell; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：拟议研究的目标是探索表面装饰有非天然氟化碳水化合物的活细胞的生物学和生物物理学特性。已经发现，这种细胞表面修饰降低了细胞粘附，因此可以提供治疗由细胞粘附介导的人类疾病过程如肿瘤转移和炎症的手段。本项目的一部分旨在确定细胞表面氟修饰对与细胞粘附相关的生物功能的影响。将通过小鼠模型中的生物发光成像来研究氟化唾液酸降低肿瘤转移速率或程度的能力。通过将细胞与化学合成的氟化唾液酸类似物一起孵育来实现氟化分子与细胞表面的附着，所述氟化唾液酸类似物被吸收并加工成在细胞糖萼上表达的氟化糖蛋白和糖脂。该项目的一部分是确定氟化唾液酸类似物在细胞表面表达的结构要求。此外，修饰分子在细胞表面上的分布和性质将通过二次离子质谱法、通过选择性切割的细胞表面分子的比色测定和通过化学遗传学方法来确定。由于氟化分子在未修饰的细胞中几乎不存在，因此氟原子的掺入为通过非侵入性技术进行低背景成像提供了机会。用氟化唾液酸处理的荷瘤小鼠将通过19 F MRI成像。由于许多肿瘤细胞是高度唾液酸化的，这种技术可能有助于在肿瘤通过其他手段可见之前定位肿瘤。本研究的具体目的是：（1）确定在培养细胞上表达的氟化唾液酸类似物的耐受范围;（2）评价表达氟化唾液酸的细胞的静态粘附特征并研究粘附改变的机制;（3）表征表达氟化碳水化合物的细胞表面;（4）评估细胞表面修饰对小鼠肿瘤转移的影响;和（5）评估表达氟化碳水化合物的含肿瘤小鼠的19 F MRI。公共卫生关系：这项研究与癌症治疗相关，并可能与炎症性疾病相关，因为它探索了一种减少细胞粘附的新策略。这项研究也与癌症诊断有关，因为它可能提供一种通过MRI对肿瘤进行成像的方法。

项目成果

Modulation of cellular adhesion by glycoengineering.

• DOI: 10.1021/jm100374g
• 发表时间: 2010-05-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Dafik L;d'Alarcao M;Kumar K
• 通讯作者: Kumar K

Total synthesis of trifluorobutyryl-modified, globally protected sialyl Lewis x by a convergent [2+2] approach.

• DOI: 10.1016/j.tetlet.2014.11.029
• 发表时间: 2015-01-01
• 期刊: Tetrahedron letters
• 影响因子: 1.8
• 作者: Akçay G;Ramphal JY;d'Alarcao M;Kumar K
• 通讯作者: Kumar K

Fluorogenic sialic acid glycosides for quantification of sialidase activity upon unnatural substrates.

荧光唾液酸糖苷，用于定量非天然底物上的唾液酸酶活性。

• DOI: 10.1016/j.bmcl.2013.03.076
• 发表时间: 2013
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Zamora,CristinaY;d'Alarcao,Marc;Kumar,Krishna
• 通讯作者: Kumar,Krishna

Fluorination of mammalian cell surfaces via the sialic acid biosynthetic pathway.

• DOI: 10.1016/j.bmcl.2008.09.010
• 发表时间: 2008-11-15
• 期刊: Bioorganic & medicinal chemistry letters
• 影响因子: 2.7
• 作者: Dafik L;d'Alarcao M;Kumar K
• 通讯作者: Kumar K

An air- and water-stable iodonium salt promoter for facile thioglycoside activation.

• DOI: 10.1021/ol5004059
• 发表时间: 2014-03-21
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Chu, An-Hsiang Adam;Minciunescu, Andrei;Montanari, Vittorio;Kumar, Krishna;Bennett, Clay S.
• 通讯作者: Bennett, Clay S.