Grant: Discovery Grants Program - Individual

Peptides, alone or as regulatory protein regions, control many biological processes. The largest pool of external peptides in the body comes from dietary proteins. The structural diversity of proteins and peptides makes them strong candidates as ligands of receptors and enzymes. Several food peptides have biological properties for controlling metabolic processes. However, the structural and cellular mechanisms by which the peptides exhibit many biological effects remain unknown. Our group focuses on the discovery of novel bioactive food peptides, including those that modulate hormones involved in glucose metabolism, e.g., islet amyloid polypeptide (IAPP). IAPP fibrillation is involved in abnormal events, including pancreatic ß-cell dysfunction and death associated with type 2 diabetes. The cytotoxicity is caused by the ability of IAPP fibrils to permeate pancreatic ß-cell membrane, destabilize membrane integrity, and initiate apoptosis. Our work showed that some food peptides have anti-IAPP fibrillation activities, one of which acted by disaggregation of mature IAPP fibrils. This Discovery grant focuses on elucidating the interaction of food peptides with IAPP and its implications in amyloid-like fibrillation and cellular processes. The work will characterize food peptides that bind different regions of IAPP monomer, e.g., amyloidogenic, membrane-binding, and self-association regions, and those that inhibit oligomer and mature fibril formation associated with IAPP-induced ß-cell toxicity. IAPP regions where the peptides bind is hypothesized to affect the equilibrium between various IAPP species, thus influencing cellular mechanisms. The study objectives are to (1) discover novel amyloid-like IAPP fibrillation inhibitors using computational and in vitro analysis of a food peptide library; (2) understand the structural basis of interaction between IAPP and the food peptides using quantitative modelling; (3) characterize the biophysical and chemical aspects of monomer-oligomer-fibril equilibrium, to elucidate the role of peptides that bind different IAPP regions during fibrillation; (4) elucidate the cellular mechanisms of the peptides on IAPP toxicity and signaling pathways using cell models; and (5) explore cross amyloid interactions and biological potentials of the food peptides. The work will lead to major insights on the molecular basis of IAPP-peptide interaction and its implications on physiological processes associated with amyloid-like fibrillation and antidiabetic mechanisms. It will also support the long-term goals of my research program, which are to understand the mechanisms, structure-function relationships, and cellular response to low doses of food-derived peptides. The proposed program will support the training of thirteen highly qualified personnel (3 PhD, 3 MSc, 2 Postdoctoral & 5 undergraduates) in food biochemistry, biomolecular science, and cell physiology, with expertise to drive the growth of Canada's bioscience sector.