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.
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.
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|Zhang, Haohai; Chan, Leo Li-Ying; Rice, William et al. (2017) Novel high-throughput cell-based hybridoma screening methodology using the Celigo Image Cytometer. J Immunol Methods 447:23-30|
|Iwase, Hayato; Liu, Hong; Li, Tao et al. (2017) Therapeutic regulation of systemic inflammation in xenograft recipients. Xenotransplantation 24:|
|Jiang, Z Gordon; Sandhu, Bynvant; Feldbrügge, Linda et al. (2017) Serum Activity of Macrophage-Derived Adenosine Deaminase 2 Is Associated With Liver Fibrosis in Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol :|
|Brown, Aaron J; Sepuru, Krishna Mohan; Rajarathnam, Krishna (2017) Structural Basis of Native CXCL7 Monomer Binding to CXCR2 Receptor N-Domain and Glycosaminoglycan Heparin. Int J Mol Sci 18:|
|Zheng, Shuo; Kummarapurugu, Apparao B; Afosah, Daniel K et al. (2017) 2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity. Am J Respir Cell Mol Biol 56:90-98|
|Longhi, Maria Serena; Vuerich, Marta; Kalbasi, Alireza et al. (2017) Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight 2:|
|Iwase, Hayato; Hara, Hidetaka; Ezzelarab, Mohamed et al. (2017) Immunological and physiological observations in baboons with life-supporting genetically engineered pig kidney grafts. Xenotransplantation 24:|
|Bi, Yiling; Might, Matthew; Vankayalapati, Hariprasad et al. (2017) Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-?-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease. Bioorg Med Chem Lett 27:2962-2966|
|Iwase, Hayato; Liu, Hong; Schmelzer, Eva et al. (2017) Transplantation of hepatocytes from genetically engineered pigs into baboons. Xenotransplantation 24:|
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