Research Interests:1. Alternate therapeutic approach in the treatment of human cancer
2. The role of glycosylation in receptor activation
3. Molecular basis of Neu1 sialidase underlying TOLL-like receptor activation in pathophysiology of infections and inflammation
4. N-Acylated Hexosamines as Nutraceuticals: From Shellfish to Algae to Mammalian Bone and Joint Health
5. Trypanosome trans-sialidase for neuronal differentiation and neuroprotection from apoptosis
Details of Research Interests:
(A) Cancer Research:
The cancer research initiated and funded by a private-sector donor was focused to evaluate an alternate therapeutic approach in the treatment of human pancreatic cancer. This approach is based on our reports identifying the key players involved in ligand-binding and receptor activation to a novel receptor-signaling platform and its targeted translation in human disease. The cancer research identified for the first time that Neu1 sialidase may be an important cancer-targeting enzyme which acts at the receptor level signaling platform on the cell surface to modulate a number of glycosylated receptors such as epidermal growth factor, nerve growth factor TrkA, insulin and TOLL-like receptors, all of which are known to play major roles in cancer. We have identified an alternate treatment strategy being in the form of a horizontal approach, of which several important cancer growth factor receptor signaling platforms, oncogenic pathways, cancer cell survival in acquired chemo-resistance and macrophage-mediated tumor progression are targeted with promising therapeutic intent. International PCT/CA2011/050690 patent filing November 04, 2011
The mammalian Toll-like receptors (TLRs) are one of the families of sensor receptors that recognize pathogen-associated molecular patterns (PAMPs). Not only are TLRs crucial sensors of microbial (e.g., viruses, bacteria and parasite) infections for innate immune cells, they also play an important role in the pathophysiology of infectious, inflammatory and autoimmune diseases. Thus, the intensity and duration of TLR responses against infections and inflammatory diseases must be tightly controlled. Although the signaling pathways of TLR sensors are well characterized, the parameters controlling interactions between the sensors and their ligands still remain poorly defined. We have recently identified a novel mechanism of TLR activation by its natural ligand, which has not been previously observed (Amith et.al. 2009 Glycoconj J). It suggests that ligand-induced TLR activation is tightly controlled by Neu1 sialidase activation. Our data indicate that Neu1 sialidase is already in complex with TLR-2, -3 and -4 receptors, and is induced upon ligand binding to either receptor. Activated Neu1 sialidase then hydrolyzes sialyl a-2,3-linked β-galactosyl residues distant from ligand binding to remove steric hinderance to TLR-4 dimerization, MyD88/TLR4 complex recruitment (Amith et.al. 2009 Cell Signaling), NFkB activation and pro-inflammatory cell responses (Amith et.al. 2009 Glycoconj J). We know that neuraminidase inhibitor Tamiflu (oseltamivir phosphate) blocks TLR ligand induced NFkB activation, nitric oxide (NO) production and pro-inflammatory cytokines (Amith et.al. 2009 Glycoconj J). We have reported to date that TLR ligand binding induces a receptor conformational change to mediate GPCR-signaling via membrane Gαi-proteins and matrix metalloproteinase-9 (MMP-9) to activate Neu1. In addition, we have identified the key players involved in the activation of nucleic acid sensing intracellular TLR-7 and -9 receptors against imiquimod and CpG oligodeoxynucleotide (ODN), respectively. It discloses a striking identical signaling paradigm as described for the cell-surface TLRs and for receptor tyrosine kinases such as Trks, epidermal growth factor and insulin. Here, Neu1 sialidase and matrix metalloproteinase-9 (MMP9) cross-talk in alliance with G-protein coupled receptor (GPCR) neuromedin-B tethered to TLR-7 and -9 receptors at the ectodomain forms a novel molecular organizational GPCR signaling platform that is essential for ligand activation of the TLRs and cellular signaling. These findings radically redefine the current dogma(s) governing the essential activating molecules tethered to nucleic acid sensing TLRs as well as to cell surface sensing TLRs, which may provide pioneering molecular targeting approaches to disease intervention strategies.
(C) Insulin receptor signaling
We have uncovered a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Our findings identify a novel insulin receptor-signaling platformthat is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling.