Polylactosamines in Development and Cancer

聚乳糖胺在发育和癌症中的作用

• 批准号: 6894707
• 负责人: MINORU FUKUDA
• 金额: $ 40.61万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6894707
• 关键词: Golgi apparatus; N acetylgalactosamine; N acetylglucosamine; athymic mouse; carcinogenesis; cell adhesion; clinical research; enzyme activity; gene targeting; genetically modified animals; glycoprotein biosynthesis; glycoprotein structure; growth /development; hexosyltransferase; high performance liquid chromatography; human tissue; in situ hybridization; metastasis; polysaccharides; protein quantitation /detection

DESCRIPTION (provided by applicant): The primary objective of the proposal is to determine the roles of poly-N-acetyllactosamines in development, cell adhesion and cancer cell metastasis. In the past few years, we have made critical progress in this field. First, we have elucidated the biosynthetic pathways of poly-N-acetyllactosamines in both branched Nglycans and branched O-glycans. Second, we have cloned a cDNA encoding a novel beta1-Nacetylglucosaminyltransferase (beta3GIcNAcT-3) that forms extended core1 0-glycans and found that this enzyme belongs to the beta1,3-N-acetylglucosaminyltransferase gene family. Third, we have demonstrated that moderately increased expression of sialyl Lewis x dramatically increases metastatic capability of cancer cells. Based on these findings, three major areas of further studies are proposed as follows: 1) Identifying beta1, 3-N-acetylglucosaminyltransferases that play major roles in the biosynthesis of various poly-N-acetyllactosaminyl glycans. The studies will determine which beta3GIcNAcTs play a major role in adding poly-N-acetyllactosamines to N- or O-glycans. The studies will also determine if beta3GIcNAcT-2 and beta3GIcNAcT-7 form different products. 2) Determining the roles of beta3GIcNAcT-3 in cell adhesion. The studies will determine the roles of beta3GIcNAcT-3 by generating mutant mice with deficient 133GlcNAcT-3 and assess functional defects in leukocytes lacking beta3GIcNAcT-3. 3) Determine the roles of poly-N-acetyllactosamines in development and tumor formation, The studies will determine if the overexpression of beta3GIcNAcT-2 facilitates tumor formation while overexpression of beta3GIcNAcT-7 suppresses tumor formation. The studies will also determine if iGnT plays critical role in development and suppressing tumor formation through the gene knockout of iGnT and analysis of development and tumor formation in those mutant mice.

描述（由申请人提供）：该提案的主要目的是确定聚-N-乙酰氨基甲胺在发育，细胞粘附和癌细胞转移中的作用。在过去的几年中，我们在这一领域取得了关键的进步。首先，我们已经阐明了分支Nglycans和分支O-Glycans中聚-N-乙酰乳胶胺的生物合成途径。其次，我们已经克隆了一个编码新型的beta1-奈乙酰葡萄糖氨基转移酶（beta3gicnact-3）的cDNA，该蛋白酶氨基氨基转移酶（beta3gicnact-3）形成了扩展的core1 0-糖果，并发现该酶属于β11,3-n-乙酰基果糖氨基氨基氨基转移酶基因家族。第三，我们已经证明，siAllyl路易斯X的表达中等增加会显着提高癌细胞的转移能力。根据这些发现，提出了三个主要研究的主要领域，如下所示：1）识别β1，3-N-乙酰葡萄糖氨基转移酶，它们在各种多聚-N-乙酰乳乙酰基聚糖的生物合成中起主要作用。研究将确定哪些β3Gicnacts在将n-或O-聚糖中添加聚-N-乙酰氨基甲胺中起主要作用。研究还将确定beta3gicnact-2和beta3gicnact-7是否形成不同的产品。 2）确定β3GicNACT-3在细胞粘附中的作用。研究将通过产生缺乏133GlcNACT-3的突变小鼠来确定β3GicnAct-3的作用，并评估缺乏beta3gicnact-3的白细胞中的功能缺陷。 3）确定聚-N-乙酰氨基甲胺在发育和肿瘤形成中的作用，研究将确定β3GicNACT-2的过表达是否促进了肿瘤的形成，而beta3gicnact-7的过表达抑制了肿瘤的形成。这些研究还将确定IGNT是否通过IGNT的基因敲除以及对这些突变小鼠的发育和肿瘤形成的分析在发育和抑制肿瘤形成中起关键作用。