CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE

硫酸乙酰肝素的化学和生物学

• 批准号: 9277558
• 负责人: Umesh Ramanlal Desai
• 金额: $ 229.73万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-23 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277558
• 关键词: Address; Analytical Chemistry; Animal Welfare; Anticoagulants; Area; Award; Biochemical; Biology; Biophysics; Budgets; Businesses; Cell Line; Certification; Chemistry; Cities; Clinical; Clinical Trials; Code; Country; County; Development; Direct Costs; Disease; Doctor of Philosophy; Economically Deprived Population; Electronic Mail; Embryo; Enzymes; Face; First Name; Fostering; Future Teacher; Glycosaminoglycans; Goals; Hemostatic function; Heparin; Heparin Cofactor II; Heparitin Sulfate; Human Resources; Human Subject Research; In Vitro; Infection; Inflammation; Inflammation Process; Inflammatory; Institutes; Instruction; Knowledge; Laboratories; Last Name; Libraries; Location; Mentors; Methods; Modeling; NIH Program Announcements; Names; Neutrophil Infiltration; Pathologic; Pharmaceutical Chemistry; Phase III Clinical Trials; Polysaccharides; Positioning Attribute; Principal Investigator; Privatization; Process; Proteins; Province; Recombinant Proteins; Registries; Regulation; Request for Applications; Research; Research Personnel; Resource Development; Resource Sharing; Role; Scientist; Sepsis; Services; Site; Sodium Chloride; Structure; Students; Synthesis Chemistry; Technology; Therapeutic Uses; Thrombosis; Time; United States National Institutes of Health; Universities; Utah; Vertebrates; Virginia; Woman; Xenograft procedure; angiogenesis; biochemical tools; biophysical tools; chemokine; computational chemistry; computerized tools; cost; design; drug discovery; human embryonic stem cell; in vivo; in vivo Model; inhibitor/antagonist; lung injury; multidisciplinary; novel; performance site; professor; programs; response; skill acquisition; social; stem; structural biology; tool; xylosides

DESCRIPTION (provided by applicant): This 'The Chemistry and Biology of Heparan Sulfate' proposal is in response to the RFA entitled "Programs of Excellence in Glycosciences (PEG)" (HL-10-026). This PEG consists of four inter-related projects: Project I (Project Leader [PL]: K. Balagurunathan, Univ. of Utah, Salt Lake City, UT) focuses on chemo-enzymatic and 'Click' xyloside-induced synthesis for novel, structurally defined GAGs; Investigating the regulation of HS biosynthetic process and the significance of GAG chain valency; elucidating angiogenesis effects of designed GAGs; and developing inhibitors of HS biosynthetic enzymes to regulate H/HS synthesis in vivo; Project II (PL: U. Desai; Co-Investigators: D. Tollefsen and V. Yadavalli) focuses on elucidating the role of specific and non-specific interactions of H/HS with proteins using computational, biochemical and biophysical technologies; designing specific GAG activators of heparin cofactor II; and developing selected GAGs as clinically useful anticoagulants; Project III (PL: K. Rajarathnam; Co- Investigators: R. Garofalo and J. Iwahara) focuses on understanding the interaction of chemokines with designed H/HS structures using biophysical and structural methods, and developing H/HS structures that modulate neutrophil recruitment process of inflammation occurring in pathological states such as sepsis, lung injury and infection; and Project IV (PL: D. Cooper; Co-Investigators: S. Robson, R. Pierson and A. Azimzadeh) focuses on investigating designed and chemoenzymatically synthesized H/HS agents as anticoagulants in in vitro, ex vivo and in vivo xenotransplantation (xenoTx) models. The central research goals of the PEG utilizes synthetic, computational and analytical chemistry of glycosaminoglycans (GAGs), especially heparin/heparan sulfate (H/HS), to understand their role in modulating hemostasis, thrombosis, inflammation, and angiogenesis, and develop selected agents for use in thrombotic disorders, inflammatory disorders and xenotransplantation. The central skills development goal of the PEG is to mentor three assistant professors, six senior researchers and many other students to be successful glycoscience scientists and mentors. The key resource development goal of this PEG is to develop and make available a library of H/HS structures, computational tools, recombinant proteins, biochemical and biophysical tools and in vitro, ex vivo and in vivo models for GAG studies. This PEG is, thus, a unique, direct and complete effort to discover structurally distinct H/HS for therapeutic use, foster the development of young glycoscience investigators for future faculty positions and establish a shared resource with diverse range of multi-disciplinary glycan research tools. RELEVANCE: This research focuses on synthetic, computational and analytical chemistry of glycosaminoglycans (GAGs), especially heparin/heparan sulfate (H/HS), to understand their role in modulating hemostasis, thrombosis, inflammation, and angiogenesis, and develop selected agents for use in thrombotic and inflammatory disorders, and xenotransplantation. (End of Abstract)

描述（由申请人提供）：此“硫酸乙酰肝素的化学和生物学”提案是对题为“糖科学卓越计划 (PEG)”(HL-10-026) 的 RFA 的回应。该 PEG 由四个相互关联的项目组成： 项目 I（项目负责人 [PL]：犹他州盐湖城犹他大学 K. Balagurunathan）专注于化学酶法和“点击”木糖苷诱导合成，用于新型、结构明确的 GAG；研究HS生物合成过程的调控及GAG链价态的意义；阐明设计的 GAG 的血管生成作用；开发HS生物合成酶抑制剂以调节体内H/HS合成；项目 II（PL：U. Desai；联合研究员：D. Tollefsen 和 V. Yadavalli）侧重于利用计算、生化和生物物理技术阐明 H/HS 与蛋白质的特异性和非特异性相互作用的作用；设计肝素辅因子 II 的特异性 GAG 激活剂；开发选定的 GAG 作为临床上有用的抗凝剂；项目 III（PL：K. Rajarathnam；联合研究员：R. Garofalo 和 J. Iwahara）侧重于使用生物物理和结构方法了解趋化因子与设计的 H/HS 结构的相互作用，并开发调节中性粒细胞募集的 H/HS 结构败血症、肺损伤、感染等病理状态下发生的炎症过程；项目 IV（PL：D. Cooper；联合研究者：S. Robson、R. Pierson 和 A. Azimzadeh）重点研究设计和化学酶合成的 H/HS 制剂作为体外、离体和体内异种移植中的抗凝剂。 xenoTx）模型。 PEG 的中心研究目标是利用糖胺聚糖 (GAG)，特别是肝素/硫酸乙酰肝素 (H/HS) 的合成、计算和分析化学，了解它们在调节止血、血栓形成、炎症和血管生成中的作用，并开发选定的药物用于血栓性疾病、炎症性疾病和异种移植。 PEG 的核心技能发展目标是指导三名助理教授、六名高级研究人员和许多其他学生成为成功的糖科学科学家和导师。该 PEG 的关键资源开发目标是开发并提供 H/HS 结构库、计算工具、重组蛋白、生化和生物物理工具以及用于 GAG 研究的体外、离体和体内模型。因此，该 PEG 是一项独特、直接和完整的努力，旨在发现用于治疗用途的结构不同的 H/HS，促进年轻糖科学研究人员为未来的教职职位的发展，并与各种多学科聚糖研究工具建立共享资源。相关性：本研究重点关注糖胺聚糖 (GAG)，特别是肝素/硫酸乙酰肝素 (H/HS) 的合成、计算和分析化学，以了解它们在调节止血、血栓形成、炎症和血管生成中的作用，并开发选定的药物以供使用血栓和炎症性疾病以及异种移植。 （摘要完）

项目成果

Plasmin regulation through allosteric, sulfated, small molecules.

通过变构、硫酸化、小分子调节纤溶酶。

• 发表时间: 2015-01-05
• 作者: Al;Karuturi, Rajesh;White, Domonique T;Desai, Umesh R
• 通讯作者: Desai, Umesh R

CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine: STRUCTURAL EVIDENCE FOR TWO DISTINCT NON-OVERLAPPING BINDING DOMAINS.

CXCL1/MGSA 是一种新型糖胺聚糖 (GAG) 结合趋化因子：两个不同的非重叠结合域的结构证据。

• 发表时间: 2016-02-19
• 作者: Sepuru, Krishna Mohan;Rajarathnam, Krishna
• 通讯作者: Rajarathnam, Krishna

CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease.

CD39 介导的 Th17 细胞效应功能调节在青少年自身免疫性肝病中受损。

• 发表时间: 2016-08
• 影响因子: 12.8
• 作者: Liberal, Rodrigo;Grant, Charlotte R;Ma, Yun;Csizmadia, Eva;Jiang, Zhenghui Gordon;Heneghan, Michael A;Yee, Eric U;Mieli;Vergani, Diego;Robson, Simon C;Longhi, Maria Serena
• 通讯作者: Longhi, Maria Serena

Distribution of non-gal antigens in pig cornea: relevance to corneal xenotransplantation.

猪角膜中非半乳糖抗原的分布：与角膜异种移植的相关性。

• 发表时间: 2014-04
• 影响因子: 2.8
• 作者: Cohen, David;Miyagawa, Yuko;Mehra, Ruhina;Lee, Whayoung;Isse, Kumiko;Long, Cassandra;Ayares, David L;Cooper, David K C;Hara, Hidetaka
• 通讯作者: Hara, Hidetaka

Sox17 is essential for proper formation of the marginal zone of extraembryonic endoderm adjacent to a developing mouse placental disk.

Sox17 对于与发育中的小鼠胎盘相邻的胚胎外内胚层边缘区的正确形成至关重要。

• 发表时间: 2018-09-01
• 影响因子: 3.6
• 作者: Igarashi, Hitomi;Uemura, Mami;Hiramatsu, Ryuji;Hiramatsu, Ryuto;Segami, Saki;Pattarapanawan, Montri;Hirate, Yoshikazu;Yoshimura, Yuki;Hashimoto, Haruo;Higashiyama, Hiroki;Sumitomo, Hiroyuki;Kurohmaru, Masamichi;Saijoh, Yukio;Suemizu, Hiroshi
• 通讯作者: Suemizu, Hiroshi