Contact info

Dr Ashok K. Srivastava
CRCHUM � Pavillon R
900, Saint-Denis � Room R08.430
Montreal, QC H2X 0A9

Tel: 1-514-890-8000, ext. 23604
E-mail: [email protected]

Research keywords

Dr Ashok K. Srivastava is a Professor at the Department of Medicine, Universit� de Montr�al, and Head of the Laboratory of Cell Signaling at the Research Center of the Centre hospitalier de l'Universit� de Montr�al (CHUM). He obtained his PhD degree in 1974 from Kanpur University, Kanpur, India, based on the research done at the Central Drug Research Institute in Lucknow, India. Dr Srivastava received post-doctoral training at the Department of Biochemistry, University of Southern California, Los Angeles, and at the Vanderbilt University, Nashville, Tennessee. In 1981, he joined the Clinical Research Institute of Montreal as a Senior Investigator in the Diabetes and Metabolism research group. In 1992, Dr Srivastava moved to the Research Center of the CHUM as a Research Scientist. In 1998, he was appointed Associate Professor of Medicine at the Universit� de Montr�al, and was subsequently promoted to Professor of Medicine in 2005.

Dr Srivastava has published more than 60 full-length papers, 11 book chapters and has edited 3 books. He has contributed in the training of many graduate students and post-doctoral fellows. He is a member of several scientific societies, including the American Society of Biochemistry and Molecular Biology, the Canadian Society of Biochemistry and Molecular Biology, and the International Society for Heart Research. Dr Srivastava has served or is serving as a guest editor of many journals, such as Antioxidant and Redox Signaling, Canadian Journal of Physiology and Pharmacology, Cell Biochemistry and Biophysics and Molecular and Cellular Biochemistry, and is currently a member of the editorial board of Advances in Biochemistry in health and disease. He has also organized several international symposia and workshops, and also serves on the grant review panels of the Canadian Institutes of Health Research, the Heart and Stroke Foundation and the National Institutes of Health.

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Dr Srivastava's laboratory has provided novel insights on the mechanism of antidiabetic and insulinomimetic effects of vanadium-based protein tyrosine phosphatase inhibitors. They have discovered that insulin-like effects of these compounds are exerted through an insulin receptor-independent process. They have also demonstrated an essential role of insulin-like growth factor receptor (IGF1-R) transactivation in triggering organo-vanadium compound-induced gluco-regulatory signal transduction pathway in liver derived cells.

Dr Srivastava's laboratory has also demonstrated that reactive oxygen species (ROS) modulate insulin, vanadium, and vasoactive peptide-induced signal transduction pathways and thereby suggested an involvement of oxidative stress-induced signalling events in cardiovascular complications of diabetes. Ongoing studies along these lines in his laboratory would help to identify new targets to develop novel therapies for diabetes.

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1) Metals as insulin mimetics and/or insulin enhancers

Despite the availability of a host of therapeutic approaches to treat diabetes, the incidence of diabetic complications is on the rise, on a global scale. Therefore, there is a great interest to find new and more effective treatments for diabetes, and to elucidate the precise molecular mechanism of diabetes-associated secondary complications.

In this regard, several metal ions have emerged as having potent insulin-like effects in both in vitro and in vivo systems. More specifically, compounds of vanadium, zinc, and chromium have shown great promise. Our laboratory has demonstrated that inorganic vanadium compounds exert their insulin-like effects on glucose transport and glycogen synthesis through activation of key elements of insulin signal transduction pathways. However, vanadium-induced effects on these signalling events are independent of the protein tyrosine kinase (PTK) activity of the insulin receptor but require transactivation of insulin-like growth factor-1 receptor (IGF-1R). We have also discovered that organo-vanadium compounds induce the tyrosine phosphorylation of several proteins in hepatocytes, which are attenuated by pharmacological inhibition of IGF-1R-PTK activity.

Currently, one of the goals of our laboratory is to understand the precise mechanism by which vanadium compounds induce IGF1-R phosphorylation and to identify and characterise the phosphotyrosyl proteins induced by these compounds. In addition, since vanadium compounds are potent inhibitors of protein tyrosine phosphatases (PTPase), we are also attempting to identify the potential PTPase(s) targeted by these compounds in insulin sensitive tissues.

2) Hyperglycaemia, oxidative stress and cardiovascular complications

The majority of the complications of diabetes are cardiovascular in nature, and an increased generation of reactive oxygen species (ROS) due to hyperglycaemia and/or an upregulated endothelin-1 (ET-1) system has been implicated in the pathogenesis of these complications. However, the precise mechanisms by which ROS and ET-1 contribute to the development of these diseases are not fully characterized. ROS and ET-1 have been shown to activate several signalling protein kinases, such as extracellular signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (PKB) in different cell types, notably in vascular smooth muscle cells (VSMC). Since these pathways regulate cellular mitogenesis, migration, proliferation, survival and death responses, their aberrant activation has been suggested to play a role in the pathogenic mechanisms of leading vascular pathologies associated with diabetes. We have shown recently that transactivation of IGF1-R and src family PTKs are required to trigger H₂O₂-induced signalling events in VSMC. We are currently focussing our efforts to determine if transactivation of IGF1-R or other growth factor receptor or src family PTKs are also critical in triggering ET-1 and hyperglycaemic-induced signal transduction pathways.

Our research efforts are also directed towards investigating if vessels from diet-induced or genetic models of insulin resistance induced hypertension exhibit a heightened expression/activation of growth factor receptor/src family PTKs, and if pharmacological inhibition of these protein kinases would exert a beneficial effect in these models.