Roles of Sulfated Glycans in Lymphocyte Recruitment and Tumor Angiogenesis

硫酸化聚糖在淋巴细胞募集和肿瘤血管生成中的作用

基本信息

批准号：
7534122
负责人：
MINORU FUKUDA
金额：
$ 27.45万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7534122
关键词：
Adhesions Area Binding Carbohydrates Cell Communication Cell surface Cells Chronic Collaborations Contact hypersensitivity Cornea EXT1 gene Embryo Embryonic Development Enzymes Funding Generations Glycoproteins Goals Growth Factor Heparitin Sulfate Homing Inflammation Inflammatory Response Inorganic Sulfates Knockout Mice L-Selectin Laboratories Ligands Lymphocyte Lymphocyte Activation Lymphoid Mucins Mus Mutant Strains Mice Natural Killer Cells Neoplasm Metastasis Oligosaccharides Organ Play Polymerase Polysaccharides Recruitment Activity Role Simplexvirus Staging Structure Tumor Angiogenesis Unspecified or Sulfate Ion Sulfates angiogenesis base chemokine lymph nodes mouse model novel promoter receptor sialyl-2-3-(6&apos -sulfo)galactosyl-1-4-(fucopyranosyl-1-3)-N-acetylglucosamine sulfation sulfotransferase trafficking tumor tumor progression

Adhesions Area Binding Carbohydrates Cell Communication Cell surface Cells Chronic Collaborations Contact hypersensitivity Cornea EXT1 gene Embryo Embryonic Development Enzymes Funding Generations Glycoproteins Goals Growth Factor Heparitin Sulfate Homing Inflammation Inflammatory Response Inorganic Sulfates Knockout Mice L-Selectin Laboratories Ligands Lymphocyte Lymphocyte Activation Lymphoid Mucins Mus Mutant Strains Mice Natural Killer Cells Neoplasm Metastasis Oligosaccharides Organ Play Polymerase Polysaccharides Recruitment Activity Role Simplexvirus Staging Structure Tumor Angiogenesis Unspecified or Sulfate Ion Sulfates angiogenesis base chemokine lymph nodes mouse model novel promoter receptor sialyl-2-3-(6&apos -sulfo)galactosyl-1-4-(fucopyranosyl-1-3)-N-acetylglucosamine sulfation sulfotransferase trafficking tumor tumor progression

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项目摘要

In the previous funding period, we have made important progress in this field. First, we discovered that 6-sulfo sialyl Lewis X plays a major role in lymphocyte homing by generating mutant mice deficient with two sulfotransferases GlcNAc6ST-1 and GlcNAc6ST-2. Second, we discovered that 6-sulfo sialyl Lewis X on /V-glycans, as well as on O-glycans play a substantial role as lymphocyte recruitment in inflammatory response and lymphocyte homing. Third, we discovered that natural killer (NK) cells are recruited to suppress tumor formation in draining lymph nodes and this NK cell recruitment requires interaction between L-selectin on NK cells and L-selectin ligands on lymph node HEV. Fourth, we discovered that by generating mutant mice deficient in EXT1 heparan sulfate synthase, heparan sulfate plays an essential role in embryonic development on various glycans and store chemokines necessary for lymphocyte activation. Based on these findings, two major areas of study are proposed: 1. Roles of 6-sulfo sialyl Lewis X-capping structures and O-glycans carrying 6-sulfo sialyl Lewis X in lymphocyte recruitment in inflammatory response. These studies will utilize two doubly deficient mouse models, GlcNAc6ST-1/GlcNAc6ST-2, and Corel-|33GlcNAcT/Core2GlcNAc6ST-1 to determine the function of sulfation and A/-glycan-based L-selectin ligands in chronic inflammation. 2. Roles of heparan sulfate in chemokine presentation during lymphocyte recruitment and growth factor presentation during tumor angiogenesis. The studies will utilize Tie2-directed inducible EXT1 deficient mice, which we just established, to determine the function of heparan sulfate in lymphocyte rolling and activation, and tumor progression through angiogenesis. These studies will be greatly facilitated by collaboration with Drs. Michiko Fukuda, John Lowe, Peter Seeberger, and Ulrich von Andrian. These studies will help us understand the structure and function of cell surface carbohydrates in inflammatory response and tumor progression and metastasis.

在上一个资金期间，我们在这一领域取得了重要进展。首先，我们发现 6-硫siallyl刘易斯X通过产生缺乏的突变小鼠在淋巴细胞寄居中起着重要作用两个磺胺转移酶GlcNAC6ST-1和GlcNAC6ST-2。其次，我们发现6-硫磺Siallyl Lewis X ON /V-Glycans以及O-Glycans在淋巴细胞募集中起着重要作用炎症反应和淋巴细胞托管。第三，我们发现自然杀手（NK）细胞是招募以抑制排水淋巴结中的肿瘤形成，而这种NK细胞募集需要 L-选择素在NK细胞上的相互作用与淋巴结HEV上的L-选择素配体之间的相互作用。第四，我们发现，通过产生缺乏Ext1硫酸乙酰肝素合酶乙酰肝素的突变小鼠必要用于淋巴细胞激活。根据这些发现，提出了两个主要的研究领域： 1。6-硫磺Siallyl Lewis X盖结构和携带6-硫磺Siallyl Lewis X的O-聚糖的作用炎症反应中的淋巴细胞募集。这些研究将利用两个双重缺陷鼠标模型，glcnac6st-1/glcnac6st-2，corel- | 33glcnact/core2glcnac6st-1 to 确定硫酸化和基于A/ - 聚糖的L-选择蛋白配体在慢性炎症中的功能。 2。在淋巴细胞募集和生长因子过程中，硫酸乙酰肝素在趋化因子表现中的作用肿瘤血管生成期间的表现。研究将利用TIE2定向诱导的Ext1 我们刚刚建立的不足小鼠以确定硫酸乙酰肝素在淋巴细胞中的功能滚动和激活以及通过血管生成的肿瘤进展。与DRS的合作将极大地促进这些研究。 Michiko Fukuda，John Lowe，Peter Seeberger和Ulrich von Andrian。这些研究将帮助我们了解细胞表面碳水化合物在炎症反应，肿瘤进展和转移中。