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Overarching Sasisekharan Lab Initiatives

Our work has spanned from the human dimensions of the heparin crisis past us (with our identification of the contaminant and determining its biological mechanisms; [39, 40, 41]), however, with lingering unresolved questions. We focused on some of these unresolved issues that appeared most critical from a public health point of view as well as that of the US regulatory agencies.

A significant extension was the development of novel, integrated tools to study both glycans and the proteins to which they bind. The ability to clarify nuances of glycan topology in the context of human adaptation was only possible by deploying diverse tools to study both the glycan and protein in the influenza system. We were able to apply these approaches in real-time for the rapidly evolving public health problem with the outbreak of 2009 H1N1. More recently, we investigated these properties in the context of H7N9 bird influenza virus. We are also building on our established experience and collaboration (with Dr. Ian Wilson TSRI, San Diego and Dr. Torri, Ronzoni Institute, Italy) for x-ray structure and NMR studies respectively on glycan-HA interactions. These approaches provides unique constraints on the dynamics of glycan motion imposed by a binding site or active site in the protein. On the protein side we are defining HA RBS as features that go beyond hallmark amino acids in governing receptor specificity. We are correlating RBS features with experimental glycan-binding properties. Our approach would permit new insights into specificity of HA-glycan interactions from the standpoint of structural constraints imposed by HA on glycan motion in context of naturally evolving (H1, H3 H5, H7, H9) HA sequences going beyond conventional structure-function relationships.

It has become ever clearer to us that, to truly understand glycan-protein interactions, the more examples we are able to study the better able we are to capture the diversity of these systems. In that context, we are expanding our glycomics efforts to focus on a “systems” approach employing a genetic multistage model of non-small cell lung cancer in collaboration with Dr. Tyler Jacks’ group, Koch Institute, MIT. We employ cell lines derived from the K-ras LSL-G12D/+; p53flox/flox (hereafter KP) mouse model of NSCLC developed by the Jacks lab. In this analysis, we are examining differences between non-metastatic and metastatic cell lines in gene expression profiles of all the enzymes involved in biosynthesis of N- and O-linked glycans and correlate these with the substrate-product profile that we have already compiled for human and murine enzymes. Second, we are employing our integrated glycomics analyses to identify fine structural features (through mass spectrometry) and location of specific structural motifs (through lectin-based staining). Third, we are analyzing the various extracellular components of the tumor microenviroment through genomic and proteomic analysis of the tumor isolated from mice. We are also applying the tools the Sasisekharan laboratory has developed to the emerging Cancer Stem Cell (CSCs) arena in collaboration with Dr. Robert Weinberg’s group (Whitehead Institute, MIT). CSCs have emerged as the drivers of cancer initiation and metastasis in multiple cancer types, including Breast Cancer (BrCa). Despite their clinical importance, the biological mechanisms promoting CSC initiation and maintenance remain largely unknown.

The Sasisekharan Lab in Singapore (ID-IRG, SMART) is building antibody platforms to tackle various infectious diseases, including Influenza and Dengue.

As a part of the Skoltech initiative (Skoltech Center for Innovative Biomedical Therapies), Sasisekharan Lab collaborates with Moscow State University on various infectious Disease targets.

In collaboration with the Princess Chulabhorn Research Institute, Sasisekharan Lab is developing newer platforms for drug development.