Grant: CIHR/Regional Partnership Program/Operating Grants

While the consumption of fast food with a high sugar and fat has been increasing worldwide, the metabolic disorders (diabetes, obesity and hypertension) have also been increased markedly during the past decade. Recent data from WHO indicate that worldwide nearly one billion people have hypertension and 250 million people have diabetes. By 2025, the total number of patients with hypertension or diabetes is expected to grow to 1.5 billion and 380 million, respectively. Therefore, finding the causes and mechanisms, and developing potent therapeutic interventions are critical for decreasing the morbidity and mortality caused by these diseases. One finger print of hypertension or diabetes is the increased production of methylglyoxal (MG), a metabolite of sugar and fat, in the circulation and cardiovascular tissues. This research project will specifically explore cellular and molecular mechanisms underlying MG-induced over-proliferation of vascular smooth muscle cells. In particular, how Akt1, a cell growth regulator, mediates the cellular effect of MG will be explored. We propose that reaction of MG and Akt1 links MG and Akt1 together, namely glycation of Akt1, and by doing so MG activates Akt1, resulting in an increase in cell number and thickness of blood vessel wall. Based on this hypothesis, we will further develop novel compound that can more specifically and potently bind to MG before MG interacts with Akt or other important cellular signaling molecules. Elucidating the molecular and structural interactions of MG and Akt1, and developing potential effective MG scavengers will not only shed light on the pathogenesis of MG-induced metabolic syndromes, but will also offer innovative approaches for treatment and the prevention of these metabolic disorders.