Natural biopolymers heparin and heparan sulfate play critical roles in a large number of biological processes including coagulation, growth and morphology, angiogenesis, immune response, inflammation, and pathogen invasion. In fact, heparin and its derivatives, low molecular weight heparins and fondaparinux, are clinically used as anticoagulants in a number of thrombotic disorders. The fundamental basis for the use of heparin in these disorders is its high affinity and high specificity interaction with antlthrombin, a plasma glycoprotein and inhibitor of coagulation enzymes, especially thrombin, factor Xa and factor IXa. Despite the longstanding use of heparin, it continues to suffer from a number of problems. Better heparin-based anticoagulation therapy is critically needed, especially at a time when its heterogeneous nature can also give rise to problems associated with contaminations. Additionally, although heparin and heparan sulfate play important roles in other physiological and pathological processes, no clinical agent has as yet been devised. The major reason for this state is the phenomenal structural diversity of H/HS, which results in a) the difficulty of preparing HS preparations with defined structural composition and b) the difficulty of studying the interaction of a large number of HS structures with multiple proteins. Major advances are necessary in these two areas to decode H/HS structure - function relationships so as to enable the design of agonists and/or antagonists for modulation of biological processes. This Project 11 of the PEG addresses the fundamental difficulty of studying the interactions of all possible HS sequences with any protein (i.e., area b) above) through a unique technology developed in the laboratory of the PL called combinatorial virtual library screening (CVLS) technology. In combination with Projects I, III and IV, we propose 1) to decipher fundamental aspects of HS structure - function relationships in the coagulation and inflammation system, and 2) to test this enhanced understanding in in vivo animal models, especially for the coagulation system. Thus, we propose to 1) study the importance of specific and non- specific interactions of heparan sulfate with proteins using computational approaches and identify promising structures for in vitro and in vivo investigation;2) develop computationally designed HS structures as specific activators of heparin cofactor II;and 3) investigate the interaction of designed H/HS with coagulation proteins at a molecular level for development as new clinically useful anticoagulants.

Public Health Relevance

Thrombotic disorders affect 1 in 3 individuals in the US. The proposed research involves the computational design, biochemical evaluation and animal testing of heparan sulfates as modulators of thrombotic disorders.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
United States
Zip Code
Brown, Aaron J; Sepuru, Krishna Mohan; Sawant, Kirti V et al. (2017) Platelet-Derived Chemokine CXCL7 Dimer Preferentially Exists in the Glycosaminoglycan-Bound Form: Implications for Neutrophil-Platelet Crosstalk. Front Immunol 8:1248
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; Feldbr├╝gge, 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:

Showing the most recent 10 out of 123 publications