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 #
5P01HL107152-04
Application #
8669104
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Sarkar, Rita
Project Start
2011-09-23
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$2,174,486
Indirect Cost
$191,612
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
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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
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