The Kidney Foundation of Canada

Dr. Todd R. Alexander 

Dr. Todd R. Alexander

University of Alberta, Alberta

Molecular mechanisms mediating paracellular intestinal pi absorption and the development of CVD


2017-2019:  $100,000  |  Biomedical Research Grant  |  Category: Renal Failure

Biography

Dr. Alexander is a Pediatric Nephrologist at the Stollery Children’s Hospital and Associate Professor in the Department of Pediatrics with an adjunct appointment to Physiology at the University of Alberta. Dr. Alexander completed his MD at the University of Western Ontario. Training in Pediatrics was performed at Memorial University in Newfoundland and Pediatric Nephrology at the Hospital for Sick Children. After this, he received a Ph.D. in Cell Biology from the University of Toronto. He then completed a Post-doctoral fellowship in renal tubular physiology at St Radboud University in the Netherlands. The focus of Dr. Alexander’s research is primary transport mechanisms by which the renal tubule regulates the body’s electrolyte, acid/base and calcium balance. In particular he seeks to understand the molecular mechanisms responsible for altered tubular salt absorption leading to the development of hypertension and the related process of how perturbations in tubular calcium transport induce kidney stone formation. His work is supported by the Canadian Institute of Health Research, the Natural Sciences and Engineering Research Council, the Kidney Foundation of Canada and the Women and Children’s Health Research Institute. Dr. Alexander is the Canada Research Chair (tier 2) in Renal Epithelial Transport Physiology.

Lay Summary

The most common cause of death in persons with kidney failure is cardiovascular disease. In persons with chronic kidney disease and end-stage renal disease, blood phosphate levels directly correlate with cardiovascular diseases including heart attack and stroke. This is because phosphate can bind calcium in the blood-forming calcifications in blood vessels and the subsequent sequlae; heart attack and stroke. Unfortunately, we do not completely understand, at a molecular level, how phosphate (a common food preservative) is absorbed into the blood. We aim to decipher this, so that we can block intestinal phosphate absorption thereby preventing cardiovascular diseases in persons with kidney disease. What is known is that the majority of ingested phosphate is absorbed between intestinal cells.

The Alexander laboratory has significant experience understanding the movement of substances between cells. We have observed that preventing the movement of sodium through intestinal and kidney cells prevents the movement of ions and small molecules between cells. This is because blocking sodium movement somehow makes the connection between cells tighter. In this proposal, we seek to understand how this occurs and tease out the signaling molecules mediating this, such that they can be manipulated to prevent phosphate absorption and cardiovascular disease in persons with kidney disease. This proposal also seeks to identify the proteins in the connection between intestinal cells that permits or prevents the movement of phosphate between them. The Alexander laboratory has generated mice genetically engineered to lack one such protein, called claudin-12. Preliminary data infers that claudin-12 forms a phosphate barrier between epithelial cells. This project will clearly define the role of this protein in intestinal phosphate absorption.

Further, given the proposed effect of claudin-12 on intestinal phosphate flux, i.e. it prevents it, this model will be used to examine the effect of increased intestinal phosphate absorption on the tendency to develop cardiovascular disease. Ultimately these studies will provide new therapeutic targets for the treatment of cardiovascular disease in persons with kidney disease.