Projects

The Chemistry and Biology of Heparan Sulfate
Link to HSPG-PEG website

Project 1: Defining Vascular Functions of Proteoglycans through Chemical Biology Approaches

Much remains to be known about glycosaminoglycans (GAGs) that modulate physiological and pathological responses. The project aims to prepare a body of GAG molecules that modulate the function of proteins of coagulation, inflammation and angiogenesis systems.
Transformational Aspects:

  • A powerful technology, called chemo-enzymatic synthesis of heparan sulfates (HSs), will be used for preparation of animal-free heparins that modulate coagulation and inflammation.
  • Another powerful technology, namely xyloside-mediated in vivo expression of GAGs, will be exploited for induction of GAG synthesis in model systems for modulation of physiological and/or pathological responses.

Personnel

Project 2: Computationally Designed Heparan Sulfates and Pathophysiology

The project aims to develop detailed understanding on HS binding to coagulation and inflammation proteins through powerful computational techniques, which will lead to design new molecules of therapeutic significance.
Transformational Aspects:

  • A widely applicable technology, called combinatorial virtual library screening technology, will be developed so as to enable identification of pharmacologically relevant HS molecules.
  • Specific HS structures that modulate the heparin cofactor II pathway of thrombotic regulation, chemokine – chemokine receptor interactions, and coagulation factor physiology to change the current antithrombotic therapy.

Personnel

Project 3: Heparan Sulfate – Chemokine Interactions and Inflammation

The modulation of chemokine –mediated neutrophil activation by HS, a key immune regulatory event, is being targeted for investigation. This is the first detailed molecular level investigation into how HS can modulate inflammatory events.
Transformational Aspects:

  • Designer HS decoys that modulate chemokine function will have applications in inflammatory diseases.
  • The structural and mechanistic tools developed to understand HS – chemokine complexes here will have implications for many other HS – protein interactions of importance in other physiological systems.

Personnel

Project 4: Therapeutic Assessment of Synthetic Heparan Sulfates in Transplantation Models

Genetic engineering of pigs as a source of organs for humans is considered as a powerful approach to resolve the crisis of non-availability of human organs. The project aims to assess computationally designed HS molecules to develop detailed understanding on the complex interplay between HS, coagulation factors and inflammation during xenotransplantation (xenoTx).
Transformational Aspects:

Personnel

  • David K.C. Cooper, MD/PhD (Project Leader)
  • (412) 383-6961