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

• 批准号: 8308588
• 负责人: MINORU FUKUDA
• 金额: $ 27.02万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308588
• 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; Normal Cell; 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; neoplastic cell; novel; promoter; receptor; sialyl-2-3-(6' -sulfo)galactosyl-1-4-(fucopyranosyl-1-3)-N-acetylglucosamine; sulfation; sulfotransferase; trafficking; tumor; tumor progression

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.

在上一个供资期间，我们在这一领域取得了重要进展。首先，我们发现， 6-磺基唾液酸刘易斯X在淋巴细胞归巢中起主要作用， 两种磺基转移酶GlcNAc 6ST-1和GlcNAc 6ST-2。第二，我们发现6-磺基唾液酸刘易斯 N-聚糖上的X-和O-聚糖上的X-在淋巴细胞募集中起着重要作用。 炎症反应和淋巴细胞归巢。第三，我们发现自然杀伤（NK）细胞是 募集来抑制引流淋巴结中的肿瘤形成，并且这种NK细胞募集需要 NK细胞上L-选择素与淋巴结HEV上L-选择素配体之间的相互作用。四是 发现通过产生缺乏EXT 1硫酸乙酰肝素合酶的突变小鼠， 在胚胎发育过程中对各种聚糖起着至关重要的作用，并储存必需的趋化因子 用于淋巴细胞活化。根据这些研究结果，提出了两个主要研究领域： 1. 6-磺基唾液酸刘易斯X-加帽结构和携带6-磺基唾液酸刘易斯X的O-聚糖在 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 小鼠模型，GlcNAc 6ST-1/GlcNAc 6ST-2，和Corel-|33 GlcNAcT/核心2GlcNAc 6ST-1至 确定硫酸化和基于N-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 在肿瘤血管生成期间呈现。这些研究将利用Tie 2定向的诱导型EXT 1 缺陷小鼠，我们刚刚建立，以确定硫酸乙酰肝素的功能，淋巴细胞 滚动和激活，以及通过血管生成的肿瘤进展。 这些研究将大大促进与福田康夫博士，约翰劳，彼得 Seeberger，and Ulrich von Andrian.这些研究将有助于我们了解 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。