CHEMISTRY AND BIOLOGY OF HEPARAN SULFATE

描述（由申请人提供）：本“硫酸乙酰肝素的化学和生物学”提案是对标题为“糖科学（PEG）卓越计划”（HL-10-026）的RFA的回应。本PEG由四个相互关联的项目组成：项目I（项目负责人[PL]：K. Balagurunathan，犹他州大学，湖城，UT）专注于化学-酶促和“点击”木糖苷诱导的新型结构确定的GAG的合成;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的血管生成作用;以及开发HS生物合成酶的抑制剂以调节体内H/HS合成;项目II（PL：U. Desai; Co-Investigators：D. Tollefsen和V. Yadavalli）专注于使用计算、生物化学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活化剂;并开发选择的GAG作为临床有用的抗凝剂;项目III（PL：K. Rajarathnam;共同研究者：R. Garofalo和J. Iwahara）专注于使用生物物理和结构方法理解趋化因子与设计的H/HS结构的相互作用，并开发调节在病理状态如脓毒症、肺损伤和感染中发生的炎症的中性粒细胞募集过程的H/HS结构;和Project IV（PL：D.库珀;合作研究者：S.罗布森河Pierson和A. Azimzadeh）专注于研究设计和化学酶促合成的H/HS试剂在体外、离体和体内异种移植（xenoTx）模型中作为抗凝剂。 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，以了解其在调节止血，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，炎症性疾病和异种移植的选定药物。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家和导师。该PEG的关键资源开发目标是开发和提供H/HS结构库、计算工具、重组蛋白、生物化学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，这种PEG是一种独特的，直接的和完整的努力，以发现结构上不同的H/HS用于治疗用途，促进年轻的糖科学研究人员的发展，为未来的教师职位，并建立一个共享的资源与各种多学科的聚糖研究工具。相关性：本研究的重点是糖胺聚糖（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，并开发用于血栓形成和炎症性疾病以及异种移植的选定药物。(End摘要）

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)