This is the Program Introduction and Statement of Objectives of 'The Chemistry and Biology of Heparan Sulfate'PEG. 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. It bridges the gap between chemists and biomedical researchers, as expected by the RFA.
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.
|Ezzelarab, Mohamed B; Ekser, Burcin; Azimzadeh, Agnes et al. (2015) Systemic inflammation in xenograft recipients precedes activation of coagulation. Xenotransplantation 22:32-47|
|Sepuru, Krishna Mohan; Poluri, Krishna Mohan; Rajarathnam, Krishna (2014) Solution structure of CXCL5--a novel chemokine and adipokine implicated in inflammation and obesity. PLoS One 9:e93228|
|Mehta, Akul Y; Thakkar, Jay N; Mohammed, Bassem M et al. (2014) Targeting the GPIb? binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects. J Med Chem 57:3030-9|
|Bane Jr, Charles E; Gailani, David (2014) Factor XI as a target for antithrombotic therapy. Drug Discov Today 19:1454-8|
|Kalita, Mausam; Balivada, Sivasai; Swarup, Vimal Paritosh et al. (2014) A nanosensor for ultrasensitive detection of oversulfated chondroitin sulfate contaminant in heparin. J Am Chem Soc 136:554-7|
|Rajarathnam, Krishna; Rosgen, Jorg (2014) Isothermal titration calorimetry of membrane proteins - progress and challenges. Biochim Biophys Acta 1838:69-77|
|Tran, Vy M; Kuberan, Balagurunathan (2014) Synthesis of fluorophore-tagged xylosides that prime glycosaminoglycan chains. Bioconjug Chem 25:262-8|
|Safo, Martin K; Musayev, Faik N; Mosier, Philip D et al. (2014) Crystal structures of influenza A virus matrix protein M1: variations on a theme. PLoS One 9:e109510|
|Al-Horani, Rami A; Desai, Umesh R (2014) Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. J Med Chem 57:4805-18|
|Al-Horani, Rami A; Desai, Umesh R (2014) Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders. Med Res Rev 34:1168-216|
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