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

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.

在之前的资助期间，我们在这一领域取得了重要进展。首先，我们发现 6-磺基唾液酸Lewis X通过产生缺陷小鼠，在淋巴细胞归巢中发挥重要作用两种磺基转移酶 GlcNAc6ST-1 和 GlcNAc6ST-2。其次，我们发现6-磺基唾液酸路易斯 /V-聚糖上的 X 以及 O-聚糖上的 X 在淋巴细胞招募中发挥重要作用炎症反应和淋巴细胞归巢。第三，我们发现自然杀伤（NK）细胞 NK 细胞被招募来抑制引流淋巴结中肿瘤的形成，并且这种 NK 细胞招募需要 NK 细胞上的 L-选择素与淋巴结 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 硫酸乙酰肝素合酶的突变小鼠，硫酸乙酰肝素在各种聚糖的胚胎发育中起重要作用并储存必需的趋化因子用于淋巴细胞活化。基于这些发现，提出了两个主要研究领域： 1. 6-磺基唾液酸路易斯 X 封端结构和携带 6-磺基唾液酸路易斯 X 的 O-聚糖在炎症反应中淋巴细胞的募集。这些研究将利用两个双缺陷小鼠模型、GlcNAc6ST-1/GlcNAc6ST-2 和 Corel-|33GlcNAcT/Core2GlcNAc6ST-1 确定硫酸化和基于 A/-聚糖的 L-选择素配体在慢性炎症中的功能。 2. 硫酸乙酰肝素在淋巴细胞募集和生长因子过程中趋化因子呈递中的作用肿瘤血管生成过程中的表现。该研究将利用 Tie2 定向诱导 EXT1 我们刚刚建立的缺陷小鼠，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。与博士的合作将极大地促进这些研究。福田美智子、约翰·洛、彼得西伯格和乌尔里希·冯·安德里安。这些研究将帮助我们了解其结构和功能细胞表面碳水化合物在炎症反应和肿瘤进展和转移中的作用。