Professor of Medicinal Chemistry
B.S. 1992, St. Joseph's College; M.S. 1994, Indian Institute of Technology; Ph.D. 2000, University of Iowa; Post-doctoral Fellow 2001-2004, MIT
Biological roles of Heparan Sulfate Proteoglycans in the CNS
Heparan sulfate (HS) is a ubiquitous molecular component of cell surfaces and the extracellular matrix. HS interacts with a wide variety of proteins such as growth factors, morphogens, chemokines, and many more. Their strategic location enables them to regulate many important biological processes through HS-protein interactions. Many of these interactions are essential for this class of proteins to transduce signals across the plasma membrane, which are implicated in human health and diseases. Furthermore, alterations in the biosynthesis or catabolism of HS chains are associated with various congenital and neurological disorders. The unique molecular sulfation pattern and flexibility of HS chains are essential for their ability to modulate cellular responses. However, it has been difficult to elucidate the rules that dictate such interactions that result in distinct biological responses.
We propose a chemical approach to spatiotemporally modulate biosynthetic enzymes to determine structure-function relationships. We design and synthesize a library of small molecules, and screen for their effect on the biosynthesis of HS and for the modulation of HS fine structures in model cellular systems with the aid of various analytical tools. The active molecules are then utilized in zebra fish through collaborations to decipher the role of HS in cell-signaling and in CNS development and disorders. We are also cloning and expressing various biosynthetic and catabolic enzymes to synthesize and deduce HS fine structures with a final goal to understand their biosynthetic and catabolic pathways, and their role in various physiological processes (axon guidance, regeneration, and learning and memory) and in human diseases (congenital defects, cerebral thrombosis, and CNS disorders). We anticipate that deciphering the enigmatic structures of HS and understanding their biosynthetic/catabolic pathways will lead to the development of HS-based molecular scaffolds to diagnose and tackle mental disorders.