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.

Public Health 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107152-07
Application #
9277558
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Sarkar, Rita
Project Start
2011-09-23
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2019-05-31
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Joseph, Prem Raj B; Sawant, Kirti V; Iwahara, Junji et al. (2018) Lysines and Arginines play non-redundant roles in mediating chemokine-glycosaminoglycan interactions. Sci Rep 8:12289
Kishore, Bellamkonda K; Robson, Simon C; Dwyer, Karen M (2018) CD39-adenosinergic axis in renal pathophysiology and therapeutics. Purinergic Signal 14:109-120
Boothello, Rio S; Patel, Nirmita J; Sharon, Chetna et al. (2018) A Unique Non-Saccharide Mimetic of Heparin Hexasaccharide Inhibits Colon Cancer Stem Cells via p38 MAP Kinase Activation. Mol Cancer Ther :
Abdel Aziz, May H; Desai, Umesh R (2018) Novel heparin mimetics reveal cooperativity between exosite 2 and sodium-binding site of thrombin. Thromb Res 165:61-67
Sepuru, Krishna Mohan; Iwahara, Junji; Rajarathnam, Krishna (2018) Direct detection of lysine side chain NH3+ in protein-heparin complexes using NMR spectroscopy. Analyst 143:635-638
Sepuru, Krishna Mohan; Nagarajan, Balaji; Desai, Umesh R et al. (2018) Structural basis, stoichiometry, and thermodynamics of binding of the chemokines KC and MIP2 to the glycosaminoglycan heparin. J Biol Chem 293:17817-17828
Gangji, Rahaman Navaz; Sankaranarayanan, Nehru Viji; Elste, James et al. (2018) Inhibition of Herpes Simplex Virus-1 Entry into Human Cells by Nonsaccharide Glycosaminoglycan Mimetics. ACS Med Chem Lett 9:797-802
Rajarathnam, Krishna; Sepuru, Krishna Mohan; Joseph, Prem Raj B et al. (2018) Glycosaminoglycan Interactions Fine-Tune Chemokine-Mediated Neutrophil Trafficking: Structural Insights and Molecular Mechanisms. J Histochem Cytochem 66:229-239
French, Beth M; Sendil, Selin; Sepuru, Krishna Mohan et al. (2018) Interleukin-8 mediates neutrophil-endothelial interactions in pig-to-human xenogeneic models. Xenotransplantation 25:e12385
Kidokoro, Hinako; Yonei-Tamura, Sayuri; Tamura, Koji et al. (2018) The heart tube forms and elongates through dynamic cell rearrangement coordinated with foregut extension. Development 145:

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