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Glycosphingolipid Effects on Brain Tumor Angiogenesis

鞘糖脂对脑肿瘤血管生成的影响

基本信息

批准号：
7061813
负责人：
THOMAS N SEYFRIED
金额：
$ 23.76万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7061813
关键词：
SCID mouse angiogenesis brain circulation brain neoplasms enzyme linked immunosorbent assay gangliosides gas chromatography gene expression glycosphingolipids immunomagnetic separation matrigel neoplastic growth northern blottings sialyltransferases terminal nick end labeling tissue /cell culture vascular endothelial growth factors

项目摘要

DESCRIPTION (provided by applicant): The objective of this research is to define the role of glycosphingolipids in brain tumor growth and vascularity (i.e., angiogenesis). Gangliosides are sialic acid-containing glycolipids that are enriched in plasma membranes and are shed from tumor cells into the extracellular matrix. Gangliosides may influence brain tumor angiogenesis through multiple effects on the tumor cells and tumor associated host cells, e.g., endothelial cells and macrophages. Preliminary findings from this laboratory suggest that the simple monosialoganglioside GM3 is antiangiogenic and that more complex gangliosides (GM2, GM1, GDla and GTlb) are proangiogenic in experimental mouse brain tumors. We propose that altering tumor ganglioside composition will influence tumor growth and vascularity. We will test this hypothesis by manipulating the genes for GalNAc transferase (GalNac-T) and sialyltransferase 2 (SAT-2), two essential enzymes required for the synthesis of complex gangliosides. These genes will be up-regulated or down-regulated in stable transfectants of three well-established experimental brain tumors, i.e., the mouse EPEN and CT-2A tumors and the human glioma U87. These tumors are good models for the proposed studies because they differ in ganglioside composition, vascularity, and growth rate. Control untransfected or vector transfected tumors will be compared with their stable transfectants and will be studied as solid tumors grown in vivo and as cell lines grown in vitro. The degree of tumor angiogenesis in vivo will be assessed from analysis of microvessel density, tumor growth rate, vascular endothelial growth factor (VEGF) expression, and macrophage infiltration. The mechanisms by which gangliosides influence angiogenesis will be examined using cultured endothelial cells and the Matrigel plug model of angiogenesis. The proposed research will better define the relationship between gangliosides and tumor angiogenesis and can lead to new experimental strategies for managing brain tumors.

描述（由申请人提供）：本研究的目的是确定鞘糖脂在脑肿瘤生长和血管分布中的作用（即，血管生成）。神经节苷脂是富含于质膜中并从肿瘤细胞脱落到细胞外基质中的含唾液酸的糖脂。神经节苷脂可通过对肿瘤细胞和肿瘤相关宿主细胞的多种作用来影响脑肿瘤血管生成，例如，内皮细胞和巨噬细胞。该实验室的初步发现表明，简单的单唾液酸神经节苷脂GM 3是抗血管生成的，而更复杂的神经节苷脂（GM 2，GM 1，GDla和GTlb）在实验小鼠脑肿瘤中是促血管生成的。我们认为，改变肿瘤神经节苷脂的组成将影响肿瘤的生长和血管。我们将通过操纵GalNAc转移酶（GalNac-T）和唾液酸转移酶2（SAT-2）的基因来测试这一假设，这两种酶是合成复杂神经节苷脂所必需的。这些基因将在三种成熟的实验性脑肿瘤的稳定转染子中上调或下调，即，小鼠EPEN和CT-2A肿瘤以及人胶质瘤U87。这些肿瘤是所提出的研究的良好模型，因为它们在神经节苷脂组成、血管分布和生长速率方面不同。对照未转染或载体转染的肿瘤将与其稳定转染子进行比较，并将作为体内生长的实体瘤和体外生长的细胞系进行研究。将通过分析微血管密度、肿瘤生长速率、血管内皮生长因子（VEGF）表达和巨噬细胞浸润来评估体内肿瘤血管生成的程度。神经节苷脂影响血管生成的机制将使用培养的内皮细胞和血管生成的基质胶塞模型进行检查。这项研究将更好地确定神经节苷脂和肿瘤血管生成之间的关系，并可能导致新的实验策略来管理脑肿瘤。