DEVELOPMENT AND CHARACTERIZATION OF NOVEL SIALOGLYCAN RECOGNIZING PROBES
All cells in nature are covered with a dense and complex array of sugar chains, and in vertebrates the outermost ends of the branches on this forest are capped with sugars called Sialic acids. Current methods to study this extremely important and dynamic aspect of the glycan forest are far too difficult and expensive for a non-sialic acid expert to employ. In a project supervised by Prof. Ajit Varki at UC San Diego, I am working to derive to a set of probes from the evolutionary perfected sialic acid recognizing microbial proteins. The goal of this developing project is to define a set of probes that can be made available to any bioscience investigator, who can profile the diversity of intact sialoglycome in biological samples
SGRPs probes will help scientists answering following questions:
1. Do my samples of interest (cells, tissues or proteins) express any sialic acids? If so:
2. What types of Sia linkages are present?
3. What are the major penultimate glycan sequences underlying the Sialic acids?
4. Whether sialic acids possess specific modifications?
ROLE OF SIALIC ACIDS IN PRION NEURODEGENERATION
Human prion diseases, scientifically known as ‘variant Creutzfeldt-Jakob disease’ (vCJD) are cross-species infections of prions from cattle’s prion disease (Bovine spongiform encephalopathy-BSE, or mad cow). The route of transmission of vCJD is not yet fully understood but it is generally accepted that it is transmitted through contaminated beef. Over 180,000 cases of BSE have been confirmed in cattle in the United Kingdom between 1986 and October 2004, and millions of people are expected to be silent carriers of disease worldwide. In a research team, led by Prof. Ilia Baskakov at UMB, I contributed towards the determination of prion sialylation as critical element of prion infectivity. Taking together with pioneer studies from my colleagues, my work underlines the role of sialic acids in prion transmission, lymphotropism and neuroinflammation. Our work forwarded a mechanism of early asymptomatic phase of disease explaining how sialic acids assist prion infections, immune interactions and lymphotropism. We also demonstrated that sialyltransferase inhibitors/sialidase treatments can limit prion infectivity. This research help differentiating brain and spleen residing prions on their extent of sialylation.
DESIGN AND CHARACTERIZATION OF LIPOPOLYSACCHARIDE NEUTRALIZING AND ANTIMICROBIAL PEPTIDES
It had been 50 years since first reports on anti-inflammatory properties of a peptide (polymyxin B) were published by Kyodo Iida (Kyushu University, Japan) and W. Inniss (University of Waterloo, Canada), but the structural requirements of an anti-inflammatory peptide were not identified. Under mentorship of Dr. Jimut Kanti Ghosh at CSIR-Central Drug Research Institute, I characterized role of leucine zipper motif (also known as heptadic repeat elements) and amphipathicity in anti-inflammatory properties of antimicrobial peptides. This research provided a straightforward approach to design nontoxic peptides of anti-inflammatory and antibacterial properties with high therapeutic indexes. These studies along with equivalent projects by other lab members contributed critically towards our understanding of toxicity, antibacterial and anti-inflammatory properties in natural as well as synthetic peptides. My project on Temporin L advanced the concept of 'amphipathicity over hydrophobicity' and devised strategies to enhance antibiotic and anti-inflammatory properties in small hydrophobic peptides as high as 400%.