CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE

描述(由申请人提供)：这份“硫酸乙酰肝素的化学和生物学”提案是对RFA题为“糖类科学卓越项目(PEG)”(HL-10-026)的回应。该项目由四个相互关联的项目组成：项目一(项目负责人[PL]：K.Balagurunathan，Uni.美国犹他州盐湖城大学)致力于利用化学酶和‘Click’木糖苷诱导合成新的、结构明确的GAG；研究HS生物合成过程的调节和GAG链价的意义；阐明设计的GAG的血管生成效应；开发HS生物合成酶的抑制剂以调节体内H/HS的合成；项目II(PL：U.Desai；合作研究人员：D.Tollefsen和V.Yadavalli)重点在于利用计算、生化和生物物理技术阐明H/HS与蛋白质的特定和非特异性相互作用的作用；设计肝素辅因子II的特定GAG激活剂；以及开发临床上有用的GAG；项目III(PL：K.Rajarathnam；共同研究人员：R.Garofalo和J.Iwahara)侧重于利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招募炎症过程的H/HS结构；项目IV(PL：D.Cooper；共同研究人员：S.Robson、R.Pierson和A.Azimzadeh)重点研究设计和化学酶促合成的H/HS制剂作为抗凝剂在体外、体外和体内异种移植(XexoTx)模型中的作用。聚乙二醇的中心研究目标是利用糖胺多聚糖(GAG)的合成、计算和分析化学，特别是肝素/硫酸肝素(H/HS)，了解它们在调节止血、血栓形成、炎症和血管生成中的作用，并开发用于血栓性疾病、炎症疾病和异种移植的精选药物。聚乙二醇组的核心技能培养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。该聚乙二醇组分的主要资源开发目标是开发和提供用于GAG研究的H/HS结构、计算工具、重组蛋白质、生化和生物物理工具以及体外、体外和体内模型的文库。因此，这种聚乙二醇组分是一项独特、直接和完整的努力，旨在发现用于治疗用途的结构独特的H/HS，促进年轻的糖科学研究人员为未来的教职发展，并与各种多学科的葡聚糖研究工具建立共享资源。相关性：这项研究侧重于糖胺多聚糖(GAG)的合成、计算和分析化学，特别是肝素/硫酸肝素(H/HS)，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，并开发用于血栓和炎症性疾病以及异种移植的选定药物。(摘要结束)

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)