University of Manitoba - Faculty of Medicine - Physiology

Peter C Zahradka, Professor

My laboratory has been studying the contribution of smooth muscle cell growth and migration to vascular disease. Our primary interest is in restenosis, or arterial reblockage, following mechanical intervention to remove an atherosclerotic lesion. We have identified several novel modulators of intracellular signaling that are potential targets for therapeutic intervention. Our experimental models have allowed us to identify and test selective inhibitors to examine the clinical relevance of these targets. In addition, we are employing molecular and biochemical methods to define the role of these targets. In addition, we are employing molecular and biochemical methods to define the role of these signaling intermediates in the normal blood vessel as well as following injury.Academic Achievements

B.Sc. (Biochemistry), Univ. of Western Ontario, 1978
Ph.D. (Biochemistry), Univ. of Western Ontario, 1984
Postdoctoral Fellow (Pathology), Univ. of Stanford, 1984-85
Postdoctoral Fellow (Molecular Biology and Genetics), Univ. of Guelph, 1985-89
Assistant Professor (Chemistry), Univ. of Guelph, 1989-91
Assistant Professor (Physiology), Univ. of Manitoba, 1991-97
Associate Professor (Physiology), Univ. of Manitoba, 1997-2003
Professor (Physiology), Univ. of Manitoba, 2003-present
Chair, Endocrinology and Metabolic Disease Group 2012 - present

Research Interests

The role of smooth muscle cell growth in the development of vascular disease forms the research focus of this laboratory. There is particular interest in defining mechanisms of action (cell and molecular biology) in relation to the potential for therapeutic intervention (animal models, clinical studies). An emphasis has been placed on receptor-mediated signal transduction and regulation of gene expression.

1. Angiotensin Receptors and Cell Signalling: Primary cultures of smooth muscle cells from coronary artery have permitted an analysis of the biochemical pathways that mediate gene expression, changes in smooth muscle cell phenotype and stimulate cell growth following angiotensin II receptor activation. This system has been used to establish the relative contribution of the two receptor subtypes in these cells. Furthermore, we have demonstrated that prostaglandins, MAP kinase, NF- B and PI3-kinase mediate specific intracellular signalling cascades triggered by the angiotensin receptors. Current efforts are to examine these signalling pathways in greater detail..

2. Restenosis in Response to Vascular Injury: Restenosis is characterized by the excessive growth of vascular smooth muscle cells following damage to a blood vessel during surgical procedures such as angioplasty, coronary bypass surgery and organ transplantation. A unique coronary artery organ culture system is being used to examine the stimulation of smooth muscle cell migration and growth by injury. The model has also been found ideal for testing the ability of specific compounds to prevent restenosis, which has led to further testing in an in vivo model of restenosis that employs balloon angioplasty of the porcine femoral artery. To date, several compounds have proven to have potential clinical relevance and have been identified for possible development as pharmaceuticals

3. ADP-Ribosylation: The role of protein kinases in mediating trasduction of signals from the cell surface to the nucleus is well established. Other mechanisms for signal transduction also exist, and we are the first group to identify ADP-ribosylation as a key player. Our current focus is to develop new tools for monitoring this post-translational modification, as well as to identify the cellular targets through which it operates. A major role in protein synthesis and proto-oncogene activation has been uncovered.

4. Lipid Metabolism, Diabetes and Vascular Disease: The development of atherosclerosis is closely linked to both diabetes and obesity. Diabetes also makes vascular tissues more sensitive to injury and the occurrence of restenosis is therefore elevated. What changes occur under these conditions have yet to be identified. This laboratory has been investigating the role of peroxisome proliferator-activated receptors (PPAR) as mediators of the response to insulin. As well, we have been examining the vascular effects produced by hormones released by adipose tissue (also termed adipokines). This work, in collaboration with Carla Taylor (Dept. Human Nutritional Sciences) and Asad Junaid (Section of Nephrology, St. Boniface General Hospital), forms part of a research program that includes an assessment of how nutrition and nutriceutical compounds influence adipose tissue function in relation to vascular disease, as well as diseases of other affected end organs like the kidney.