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: 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
• 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' -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.

在前一个供资期间，我们在这一领域取得了重要进展。首先，我们发现， 6-磺基唾液酸基Lewis X在淋巴细胞归巢中起主要作用 两个磺基转移酶GlcNAc6ST-1和GlcNAc6ST-2。其次，我们发现6-磺酸唾液酸基刘易斯 X-N/V-葡聚糖和O-葡聚糖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 被招募以抑制引流淋巴结中的肿瘤形成，这一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硫酸乙酰肝素合成酶的突变小鼠，硫酸乙酰肝素 在胚胎发育中起重要作用的是各种多糖和储存必要的趋化因子 用来激活淋巴细胞。基于这些发现，提出了两个主要的研究领域： 1.6-磺基唾液酸基Lewis X-封端结构和携带6-磺基唾液酸基Lewis X的O-糖链的作用 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 小鼠模型，GlcNAc6ST-1/GlcNAc6ST-2和Corel-|33GlcNAcT/Core2GlcNAc6ST-1至 确定硫酸和基于A/-葡聚糖的L-选择素配体在慢性炎症中的作用。 2.硫酸肝素在淋巴细胞募集和生长因子的趋化因子递呈中的作用 在肿瘤血管生成过程中的表现。这项研究将利用Tie2指导的可诱导EXT1 用我们刚刚建立的缺陷小鼠测定淋巴细胞中硫酸乙酰肝素的功能 滚动和激活，以及通过血管生成的肿瘤进展。 这些研究将通过与福田美智子博士、约翰·洛博士、彼得博士的合作得到极大的便利 Seeberger和Ulrich von Andrian。这些研究将帮助我们了解细胞的结构和功能。 细胞表面碳水化合物在炎症反应和肿瘤进展转移中的作用。