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Dr. Mathieu Lemaire

Award: KRESCENT New Investigator Award
Institution : The Hospital for Sick Children (SickKids)
Year : 2017-2020

Lay Summary

Dr. Mathieu Lemaire finished his medical training at McGill University in 2004 and then moved to Toronto to learn Paediatrics and Nephrology at The Hospital for Sick Children. He then went to Yale University (New Haven, CT) to pursue a PhD in Investigative Medicine under the supervision of Dr. Richard P. Lifton as a KRESCENT post-doctoral fellow.

Blood vessels are like roads that can reach any cell of our body. We call the cells that line blood vessels "endothelial cells". Blood flows fast in normal blood vessels, but it is slow when there is damage. It forms a blood clot. This is similar to a “good traffic jam”: it helps repair injured blood vessels. The body must control the machines that help with repair to avoid “bad traffic jams”. Healthy blood vessels don't need blood clots.

In the lab, we study the function of endothelial cells in the kidneys. We work on a disease called "atypical hemolytic-uremic syndrome". For simplicity, we call it "aHUS". Patients with aHUS get kidney failure. Why? Blood clots form in the blood vessels of the kidneys. These clots prevent normal blood flow in kidneys. Blood flow is important to deliver food and oxygen to the kidneys.

We found that mutations in the gene DGKE can cause aHUS. Each cell in the body contains DNA, a code made of genes. Genes make proteins—the building blocks of cells. Mutations are changes in the DNA that cause abnormal function of a protein. For our patients, the mutations prevent DGKE from working well.

DGKE is an enzyme that work on fats. DGKE stands for "diacylglycerol kinase epsilon". Diacylglycerol is also called DAG. Enzymes are like machines that do specific tasks in cells. For example, a kinase adds a phosphorus group to its target. DGKE is a kinase that targets one type of fat named DAG. Cells use DAG as a signal to turn on specific functions. It is like a light switch. When DGKE modifies DAG, it turns off the signal in the cell. When DGKE can't work, it is as if the light switch is left on too long. When that happens, patients cannot prevent blood clotting in their kidneys. These patients develop kidney failure, and we have no treatment to offer.

We study endothelial cells that have no DGKE at all. We have found three clues that help guide this project. First, we found that when DGKE does not work, it affects the function of AKT, another protein that is like a light switch. In particular, AKT turns on another protein called eNOS. Second, we also found that the function of eNOS is abnormal in cells that have no DGKE. AKT and eNOS play a major role in making sure that blood vessels stay open and are not too sticky. We don't know how DGKE deficiency causes problems with AKT and eNOS, or how this affects blood vessels. Third, we also noticed that endothelial cells that have no DGKE protein have difficulties to function normally when exposed to blood flow. The endothelial cells are like flags that are not well attached to their pole when there is high wind: they fly away leaving blood vessels without a lining.

This project will tackle four different tasks to help us understand better DGKE function in endothelial cells.

  1. Figure out how a deficiency in DGKE leads to abnormal AKT function in endothelial cells

  2. Find out how abnormal eNOS function affects the function of blood vessels that have no DGKE protein

  3. Determine how DGKE deficiency prevents endothelial cell to withstand normal blood flow

  4. Study how DGKE mutations found in patients with aHUS affect the function and structure of DGKE enzymes

This research is important so we can start thinking about new treatment for this disease. Studies on the function and structure of DGKE could be helpful to diagnose patients with new mutations. It will also teach us a lot about how normal blood vessels prevent blood clot formation..