Dr. Fernando Alvarez
CHU Sainte-Justine
Montreal, Quebec
Project Title: Depletion of B cells as a treatment for autoimmune hepatitis
Autoimmune hepatitis (AIH) is a liver disease caused by the body’s own immune system which attacks the liver resulting in inflammation and scarring. If left untreated, AIH is always fatal. AIH may present both as an aggressive form of acute hepatitis or a chronic illness that can progress to cirrhosis. Recently, Dr. Alvarez and his team have discovered that a complete remission of AIH could be achieved in some patients with an antibody (Rituximab) that temporarily destroys a type of white blood cells called B-lymphocytes. However, AIH is believed to be caused by the attack on the liver by T-lymphocytes and not by B-lymphocytes. The goal of this research is to explain the mechanisms by which destruction of B-cells help in the control of the AIH. The research findings may lead to new treatments for AIH, with fewer side effects than what is reported with current available therapy.
Dr. Klaus Gutfreund
Co-Applicant: Dr. Lorne Tyrrell
University of Alberta
Edmonton, Alberta
Project Title: Identification and targeting of inhibitory T-cell signaling pathways in the duck hepatitis B model to explore novel immunotherapeutic strategies for chronic hepatitis B.
Chronic hepatitis B affects over 350 million people worldwide and an estimated 300,000 people in Canada. Many patients with chronic hepatitis B will die due to cirrhosis and liver cancer. Current treatments with interferon alpha and oral antiviral drugs effectively suppress the virus but most patients will not maintain a long-term response to therapy. Hence, a prolonged antiviral therapy is often required which is costly and many patients eventually develop drug resistance. Therefore, finding better treatments for hepatitis B remains a priority. The purpose of this research is to develop new treatment strategies that stimulate a successful immune response to resolve chronic hepatitis B infection. Dr. Gutfreund’s team has recently developed novel genetic vaccines and identified several molecules that can be targeted to improve antiviral immune responses. The focus of this research is to further explore these promising new therapeutic vaccines, which will lead to the development of new treatments for hepatitis B patients.
Dr. Mathieu Laplante
Laval University
Quebec City, Quebec
Project Title: Determination of the role of Deptor in the development of liver cancer.
Liver cancer is one of the most common cancers worldwide. Liver cancer is resistant to both conventional chemotherapy and radiation. This leaves liver cancer patients with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools to treat this disease is needed. A protein called mTOR is known to be commonly overactivated in cancer. This protein contributes to cancer growth by promoting protein and lipid synthesis. Recently, Dr. Laplante has identified a new protein called Deptor that can inhibit mTOR. Deptor levels are low in liver cancer cells and preliminary experiments indicate that Deptor loss promotes tumour formation. The objectives of this research are to find out the role of this protein in liver cancer and to determine whether it could be targeted for the development of new treatment of liver cancer.
Dr. Andrew Mason
University of Alberta
Edmonton, Alberta
Project Title: Mouse models of genetic and environmental factors in primary biliary cirrhosis.
It is believed that primary biliary cirrhosis (PBC) results from an abnormal reaction of the body’s immune system possibly initiated by an infection. Designed to protect the body from infection, the immune system of PBC patients attacks the liver causing slow, progressive damage to the bile ducts. When the bile ducts are damaged, bile and other substances cannot be eliminated and accumulate in the liver. This eventually leads to cirrhosis. It is believed that both genetic and environmental factors may play a role in the development of PBC. Dr. Mason has recently discovered that a virus found in PBC patients resembles a mouse virus known as mouse mammary tumour virus. A mouse model has recently been developed. This model has the same immune features that have been found in patients with PBC. Dr. Mason has discovered that mouse mammary tumour virus is associated with the development of autoimmune biliary disease (similar to PBC) in these mice. Furthermore, Dr. Mason has discovered that this biliary disease can be blocked by antiviral therapy. This research should lead to the development of treatments for patients with PBC.
Dr. Christopher Richardson
Co-applicant: Dr. Eric Arts
Dalhousie University
Halifax, Nova Scotia
Project Title: Development of a novel hepatitis C virus cloning system in yeast to screen for infectious genomes and determine the role of neutralizing antibodies in viral clearance at acute infection.
Hepatitis C virus is responsible for 170 million infections worldwide and is a major cause of cirrhosis and liver cancer. However, 30% of those infected with the hepatitis C virus never develop chronic disease and get rid of the virus during the acute stage of the infection. Dr. Richardson’s research team proposes that the virus clearance is related to the rapid development of antibodies that neutralize the specific hepatitis C strains infecting the patients. This research requires the development of a unique yeast-based cloning system to produce infectious virus based on specific proteins derived from recently infected patients that either get rid of the infection of go on to develop chronic disease. Findings of this research will lead to the development of more effective treatments of chronic hepatitis C.
Dr. Naglaa Shoukry
Centre de Recherche du CHUM (Hôpital St-Luc)
Montréal, Quebec
Project Title: How does IL-28B polymorphism influence the outcome of acute hepatitis C?
Chronic hepatitis C is a major cause of liver disease and liver cancer. We still do not understand how a small fraction of people exposed to the virus can get rid of it while the rest cannot. Recent studies have established a correlation between the variations in one gene known as IL-28B and the capacity to eliminate hepatitis C infection. However, how this gene variation influences the immune response against the virus is not yet known. Dr. Shoukry believes that this gene controls the type of immune response that develops upon infection where patients who have the bad gene variant are not able to respond and consequently cannot clear the infection. The research findings will lead to the development of new treatments for hepatitis C.
Mr. Andrew Collins, McMaster University
Supervisor: Dr. Gregory Steinberg
Project title: Treating Non Alcoholic Fatty Liver Disease by Activating the AMP-activated Protein Kinase (AMPK).Non-alcoholic fatty liver disease (NAFLD) is a common condition. The growing incidence of NAFLD is tightly linked to the obesity epidemic. NAFLD can also lead to other health problems including diabetes and heart disease, and affected individuals may require a liver transplant if inflammation and liver damage develop. The number of people who develop severe liver damage is likely to increase further as the rate of childhood obesity becomes more prevalent. Fat metabolism in the liver is being regulated by an enzyme that is switched on by exercise and drugs such as metformin and aspirin. Mr. Collins will be testing whether metformin and aspirin might be effective in reversing NAFLD. The findings of this research will lead to new therapies for treating this very common liver disease which currently has no cure.
Ms. Emma Torbicki, The Hospital for Sick Children
Supervisor: Dr. Nicola Jones
Project Title: Investigating the Role of Autophagy in Ischemia Reperfusion Injury.
Currently, the short-term outcome after pediatric liver transplantation is excellent. However, the long-term outcomes for children who require liver transplantation need to be improved. During a transplant, when the liver is taken from the donor, the blood flow is cut off causing lack of oxygen. Once the organ is placed in the patient and the blood vessels reconnected, the organ receives blood once again. This results in tissue damage due to the formation of toxins and invasion by white blood cells. Recent studies indicate that a specific cellular recycling pathway called autophagy may help to remove the toxins and limit inflammation due to immune response. The results of this study will be the first step in determining if autophagy is protective in this injury that occurs in transplanted livers.
Ms. Elizabeth Kuczynski, Sunnybrook Health Sciences Centre
Supervisor: Dr. Robert Kerbel
Project Title: Reversible Resistance to Sorafenib in Hepatocellular carcinoma (HCC): Mechanisms and Implications.
Worldwide, liver cancer is the third most common cause of cancer-related deaths. Sorafenib is a drug that targets blood vessels that supply tumour with blood. However, eventually patients stop responding to drug treatment and develop resistance. Ms. Kuczynski is studying how, contrary to common perception, resistance may be reversible and not permanent. By giving a prolonged time off a drug, cancer cells can be “reset” and re-sensitized to once again respond to therapy. This research may have important implications for the clinical management of liver cancer and potentially other cancer-drug combinations in which resistance may be reversible.
Mr. Daniel Pang, University of Alberta
Supervisor: Dr. Lorne Tyrrell
Project Title: Studying Hepatitis A Virus (HAV) Infection, Replication and Clearance in a Chimeric Mouse Model.
Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two similar viruses that cause liver disease in humans. However, HAV primarily causes short-term disease while HCV usually causes long lasting disease for reasons that are not fully understood. While a better comparison of these two infections is needed, there is currently no small animal model to study HAV. Dr. Tyrrell’s lab has developed a mouse model with mixed human/mouse livers that are susceptible to HCV infections. The purpose of the study will be to test the model’s susceptibility to HAV infection and to analyze its ability to fight off infections. Mr. Pang will investigate whether the early immune response is sufficient to eliminate HAV in the mouse model. A better understanding of how we fight off HAV and HCV infections may help in the development of a preventative vaccine for hepatitis C, one of the leading causes of liver cancer.
Ms. Mandana Rahbari, University of Alberta
Supervisors: Drs. Andre Mason and Michael Houghton
Project Title: Virological Footprint of T-cell Responses in Patients with Primary Biliary Cirrhosis.
Primary biliary cirrhosis (PBC) is known as a cholestatic liver disease because it blocks or stops the flow of bile. Although PBC is a disease of unknown cause, both genetic and environmental factors may influence the development of PBC. The objective of this research is to explain the relationship between an infection with the human betaretrovirus and PBC and see if the infection with this virus plays a role in the development of PBC. This knowledge could be used to design drugs to treat PBC.
Dr. Olivier Barbier, Laval University
Pharmacological induction of hepatic glucuronidation: An efficient way to detoxify bile acids in hepatobiliary diseases.
Cholestasis, or impairment of bile flow, is one of the most devastating consequences of liver disease. Patients with this condition have extremely poor quality of life and suffer severe symptoms such as jaundice, severe itching, and fluid retention in the abdomen and legs. There are no treatments for this condition. The only cure is liver transplantation. The research project involves studying a specific metabolic detoxification pathway that eliminates bile acids through urine. The findings of this research may lead to the discovery of new treatments for cholestatic liver diseases.
Dr. Jordan Feld, University Health Network
Co-investigators: Drs. Ian McGilvray, Conrad Liles
Understanding the antiviral effects of interferon in HCV infection.
Hepatitis C is a major public health problem, affecting 200 million people worldwide, including 1-3% Canadians. Hepatitis C is a liver disease that can lead to liver failure, liver cancer and death. Although hepatitis C treatment has improved greatly, 50% of people still do not respond to current interferon-based treatment. Interferon works by activating hundreds of genes in liver cells infected with the hepatitis C virus. In many cases, these genes are able to clear the virus. To understand why interferon is not always successful in getting rid of the virus, we need to understand first how it works when it is successful. This study will focus on identifying which of the genes are necessary to clear hepatitis C infection. The research findings will lead to the development of new medications specifically targeting the antiviral genes without activating the genes that cause interferon side effects.
Dr. Kartik Jhaveri, University Health Network
Co-investigators: Drs. Sean Cleary, Sandra Fisher, Masoom Haider, Steven Gallinger
Preoperative predication of microvascular invasion in hepatocellular carcinoma by blood oxygenation level dependant magnetic resonance imaging.
Liver cancer is the fifth most common and most rapidly increasing fatal cancer in Canada. The treatment of liver cancer is complex, and cure depends on specific cancer traits, especially the spread of cancer into small blood vessels of the liver near the tumour. This spread ultimately influences patient survival. Currently this cannot be determined before treatment is undertaken. The research project will study the ability of magnetic resonance imaging (MRI) to predict such tumour spread before treatment is undertaken so that in the future the most appropriate treatment can be offered for maximum treatment benefit of the patient.
Dr. Samuel Lee, University of Calgary
Pathogenesis of cirrhotic cardiomyopathy: myosin heavy chain.
Cirrhosis due to viral hepatitis, fatty liver, autoimmune liver diseases and alcoholism is a leading cause of death and disability in Canada. Patients with cirrhosis also suffer from abnormalities of the heart. When patients with cirrhosis are put through tests to show how well the heart performs under stress, the cardiac response is blunted, suggesting the presence of a latent abnormal heart pumping function. This is known as cirrhotic cardiomyopathy (CCM). However, the underlying mechanisms remain unclear. Since the heart pumping function is impaired, it is believed that certain proteins are abnormal in CCM. This research will study if and how these proteins cause abnormal heart function. The study is significant because CCM contributes to poor outcomes for patients with cirrhosis who need liver transplantation or surgery.
Dr. Andrea Richter, Centre de recherche, Hôpital Sainte-Justine
Co-investigator: Dr. Grant Mitchell
Development of zebrafish models for North American Indian childhood cirrhosis (NAIC).
In First Nations children from Northwestern Quebec, a liver disease called North American Indian childhood cirrhosis (NAIC) is very prevalent. The only treatment available is liver transplantation. In several communities, one child out of 10 carries the gene mutation responsible for this disease. The research team identified a mutation in a protein called cirhin. The goal is to understand the function of this protein and how it causes NAIC. This research may lead to finding treatments that will eliminate the need for liver transplantation which is difficult to reconcile with traditional lifestyles in this population.
Dr. Mark Swain, University of Calgary
Regulatory role of liver recruited myeloid derived suppressor cells in response to hepatic NKT cell activation.
When the liver is exposed to hepatitis viruses, including hepatitis B and C, there is a very rapid response within the liver which is lead by a cell called the NKT cell. Activation of NKT cells in the liver results in a number of subsequent immunological events within the liver which are critical for clearing these viruses from the body. Similar events also likely occur in the early immune system response to liver cancer. However, these very early responses are hard to study in people, because patients are diagnosed with a disease long after these immune events have occurred. The research will involve studying these very early immune responses in an animal model in order to understand how they work. This will lead to the developments of new treatment for viral hepatitis.
Meghan Chow, University of Calgary (Supervisor: Dr. Mark Swain) will study the potential of probiotics in treating liver disease-related symptoms such as fatigue
Michael Doré Nguyen, CHU Sainte-Justine, Montréal (Supervisor : Dr. Fernando Alvarez) will research the risks of viral infections for children who have received liver transplants and are taking immuno-suppressive drugs.
Christian Parent-Robitaille, University of Montreal (Supervisor: Dr. Christopher Rose) will study whether hepatic encephalopathy (a symptom of advanced liver disease caused by a build-up of toxins in the brain) results in neurological problems post-transplant. Recipient of Doug Cassidy Summer Studentship Grant.
Alana Rose Sherker, University of Toronto (Supervisor: Dr. Jordan Feld) will research whether a particular protein manufactured by the immune system could help keep the hepatitis C virus from replicating.
Alissa Visram, University of Toronto (Supervisor: Dr. Jordan Feld) will study why all cancer patients are not screened for hepatitis B before undergoing chemotherapy.
Yirui Gui, Université de Sherbrooke
Supervisor : Subburaj IlangumaranRegulation of MET receptor signaling by SOCS1 in hepatocellular carcinoma.
Liver cancer is the third leading cause of cancer-related death worldwide. Dr. Gui is researching a gene that may help suppress tumour growth and could lead to gene-based therapies for liver cancer.Sally Yu Shi, University of Toronto
Supervisor: Dr. Minna Woo
The role of hepatic JAK2 in the pathogenesis of hepatocellular carcinoma.
Inflammation of the liver can lead to scarring (cirrhosis) which can in turn progress to liver cancer. Dr. Shi is studying the molecular pathways in the liver that play a role in inflammation to determine how they impact the development of liver cancer.
J.N. Kinola Williams, University of Alberta
Supervisor: Dr. Deborah Burshtyn Most patients with an acute hepatitis C infection do not develop symptoms but a large percentage will go on to develop chronic hepatitis C. Dr. Williams is researching how natural killer cells (part of the immune system’s response to attacks by viruses) respond to the hepatitis C virus and how they work with certain molecules to help clear the hepatitis C virus.
Marc Bilodeau, Université de Montréal
Co-applicants: R. Lapointe, F. Vandenbroucke
With the incidence of liver cancer on the rise, it is critical to find effective treatments for current and future patients. Unfortunately, it has been difficult to study liver cancer in a laboratory setting because there are no models of the disease that effectively mimic the tumours found in patients. Dr. Bilodeau and his team are using tissue from the tumours of liver cancer patients to grow copies of these tumours outside the body. Once it is confirmed that a model is similar enough to the patient’s actual tumour, doctors would be able to test a number of different treatments to determine what would work best for the patient.
Diana Mager, University of Alberta
Co-applicants: J. Yap, S. Gilmour, R. Tang-Wai, T.J. Snyder
When babies are born with liver diseases that interfere with bile flow, (these are known as ‘cholestatic’ liver diseases), their bodies are not able to process the nutrients – protein, fat, minerals and vitamins – from the food they eat. Starved of the fuel their bodies need to grow, these babies develop a form of malnutrition called ‘protein energy malnutrition’ or PEM. This malnutrition can cause serious delays in these babies achieving the same physical and cognitive milestones as their healthy counterparts.
Dr. Diana Mager and her colleagues are looking at ways to counteract PEM by boosting the amino acids that babies with biliary atresia (a form of cholestatic liver disease) receive prior to liver transplants.
Ran Chen, University of Alberta
Supervisor: Dr. Lorne Tyrrell
Hepatitis B and C are the major causes of liver cancer worldwide. Co-infection with the two diseases can lead to more rapid and aggressive liver disease. Ms. Chen is studying how both hepatitis B and C viruses respond to interferon which may help in the treatment of co-infected patients.
Ivan Diamond, The Hospital for Sick Children, University of Toronto
Supervisor: Dr. Paul Wales
Liver disease caused by parenteral nutrition (nutrition given directly into a vein) is known as Parenteral Nutrition Associated Liver Disease (PNALD). PNALD is common in infants with intestinal problems who need parenteral nutrition for a long time and it can eventually result in the need for a liver transplant. The omega-6 fatty acids (derived from soy beans) used in parenteral nutrition are believed to contribute to PNALD when used in isolation. Dr. Diamond is investigating whether omega-3 fatty acids (derived from fish oil) may be useful in preventing and treating PNALD.
Charmaine Ferguson, University of Toronto
Supervisor: Dr. Rachel F. Tyndale
Although smoking and alcohol consumption are recognized risk factors for the development of liver cancer, the reasons are not clear. Recent studies suggest that alcohol and nicotine can increase the levels of certain cancer-causing proteins in the liver. Mr. Ferguson is studying the levels of these proteins after several weeks of exposure to nicotine and alcohol to determine the impact on the liver.
Michael Ryczko, Mount Sinai Hospital University of Toronto
Supervisor: Dr. Jim Dennis
Carcinogens, viruses and obesity are well known causes of liver cancer. Cell growth depends on nutrient transporters and growth factor receptors located at the cell surface. Since the cell surface can adapt to environmental conditions, Mr. Ryczko is investigating the interplay between environmental and genetic factors in liver cancer initiation, progression and spread.
Raj Bhargava Summer Studentship Award
