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.
|Verespy 3rd, Stephen; Mehta, Akul Y; Afosah, Daniel et al. (2016) Allosteric Partial Inhibition of Monomeric Proteases. Sulfated Coumarins Induce Regulation, not just Inhibition, of Thrombin. Sci Rep 6:24043|
|Wood, Jeremy P; Baumann Kreuziger, Lisa M; Desai, Umesh R et al. (2016) Blocking inhibition of prothrombinase by tissue factor pathway inhibitor alpha: a procoagulant property of heparins. Br J Haematol 175:123-32|
|Holman, Holly A; Tran, Vy M; Kalita, Mausam et al. (2016) BODIPY-Conjugated Xyloside Primes Fluorescent Glycosaminoglycans in the Inner Ear of Opsanus tau. J Assoc Res Otolaryngol 17:525-540|
|Iwase, Hayato; Ekser, Burcin; Hara, Hidetaka et al. (2016) Thyroid hormone: relevance to xenotransplantation. Xenotransplantation 23:293-9|
|Mosier, Philip D; Chiang, Meng-Jung; Lin, Zhengshi et al. (2016) Broad Spectrum Anti-Influenza Agents by Inhibiting Self-Association of Matrix Protein 1. Sci Rep 6:32340|
|Sawant, Kirti V; Poluri, Krishna Mohan; Dutta, Amit K et al. (2016) Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions. Sci Rep 6:33123|
|Sepuru, Krishna Mohan; Rajarathnam, Krishna (2016) CXCL1/MGSA Is a Novel Glycosaminoglycan (GAG)-binding Chemokine: STRUCTURAL EVIDENCE FOR TWO DISTINCT NON-OVERLAPPING BINDING DOMAINS. J Biol Chem 291:4247-55|
|Mitsuhashi, Shuji; FeldbrÃ¼gge, Linda; Csizmadia, Eva et al. (2016) Luminal Extracellular Vesicles (EVs) in Inflammatory Bowel Disease (IBD) Exhibit Proinflammatory Effects on Epithelial Cells and Macrophages. Inflamm Bowel Dis 22:1587-95|
|Sepuru, Krishna Mohan; Nagarajan, Balaji; Desai, Umesh R et al. (2016) Molecular Basis of Chemokine CXCL5-Glycosaminoglycan Interactions. J Biol Chem 291:20539-50|
|Mehta, A Y; Mohammed, B M; Martin, E J et al. (2016) Allosterism-based simultaneous, dual anticoagulant and antiplatelet action: allosteric inhibitor targeting the glycoproteinÂ IbÎ±-binding and heparin-binding site of thrombin. J Thromb Haemost 14:828-38|
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