CLF Research Grant Competition Results

Operating Grant Awards

Designated Ontario Grant (sponsored by F. Pauline Spence)

Dr. Morgan Fullerton, University of Ottawa

Project Title: The regulation of cholesterol synthesis obesity-induced fatty liver.

Obesity has become a global epidemic and now affects millions of Canadians (costing almost 10 billion dollars annually). Obesity is the leading cause of numerous metabolic disorders and it is now the most common cause of fatty liver disease in Canada. Although responsible for making and processing fats and cholesterol, the liver can become overloaded with fats which is first step in fatty liver disease. It is known that cholesterol made in the liver can play an important role in the development of fatty liver, but Dr. Fullerton believes that the metabolic pathways that control the amount of cholesterol malfunction during obesity. This research proposal aims to better understand how obesity re-wires the liver to over-produce cholesterol in the hopes that we can one day prevent and correct obesity-related fatty liver disease.

Designated Liver Cancer Research Grant

Dr. Anand Ghanekar (University of Toronto, Toronto General & Western Hospital Foundation)

Project Title: Role and regulation of dual specificity phosphatase 9 (DUSP9) in human hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver cancer that starts in the liver, and is the 5th most common cancer in the world, and the 3rd leading cause of cancer-related death. Better knowledge about how HCC develops and progresses should lead to improve treatments. Dr. Ghanekar’s research has revealed that a molecule called dual specificity phosphatase 9 (DUSP9) is present at a high level in human HCC tumours. Molecules like DUSP9 are important in controlling cell growth in other cancers but have not been studied in HCC. The goal of this research is to understand the function of DUSP9 in liver cancer by studying liver cancer cells in dishes as well as in mice, and observe how their behaviours changes with modifications in DUSP9 levels and to identify the molecular mechanisms and proteins in liver cancer cells that control DUSP9 levels. The results of this study should improve our understanding of HCC and lead to opportunities for innovative treatments.

Unrestricted Hepatobiliary Research Grants

Dr. Christopher Rose (Université de Montréal CRCHUM)

Project Title: The pathophysiological mechanisms underlying the continuum of hepatic encephalopathy: from covert to overt, recurrent and persistent.

Hepatic encephalopathy (HE) is a serious neurological complication which frequently develops in patients with chronic liver disease. The mildest form of HE is called covert HE and it involves confusion and problems with memory and concentration. This can significantly impact the quality of life of people who have liver disease. When obvious clinical signs such as stupor and coma are found in patients, this is called overt HE. As much as 80% of patients with cirrhosis (scarring of the liver) suffer from covert HE and these patients have a high risk of developing recurring episodes of overt HE possibly leading to permanent brain damage. Covert HE is associated with an increase of fluid in the brain (edema) and it is not clear how and why this occurs. Build-up of ammonia in the brain is believed to play a major role since a healthy liver controls ammonia levels in the blood. When the liver is scarred, an increase in blood ammonia leads to toxic levels of ammonia in the brain. The objective of this research project is to study how an increase in ammonia levels in the blood and inflammation cause an increase in fluid in the brain and how this influences progression to overt HE. Dr. Rose will also study the impact of multiple episodes of overt HE on the brain, including permanent brain damage.

Dr. Daniel Winer, University of Toronto, Toronto General & Western Hospital Foundation

Project Title: Immune mechanisms of hepatic glucose dysregulation in diet-induced obesity and non-alcoholic fatty liver disease.

Obesity has multiple consequences including high levels of fat inside the liver. Fatty liver disease plays a major role in raising blood sugar levels, though the exact mechanisms are poorly defined. Dr. Winer’s research has shown that immune cells known as B and T cells can cause inflammation in fatty tissues, which results in metabolic disease. Dr. Winer has discovered that T cells within the liver become activated during fatty liver disease and cause inflammation and metabolic complications. However, the roles of additional immune cells in this inflammation in the liver are largely unknown. This research proposal builds on the existing work and will investigate how immune cells called B cells become major contributors to liver disease in obesity. Specifically, Dr. Winer will study how liver B cells worsen fatty liver disease and whether they can be stopped with innovative approaches. The results of this research will lead to new ways to prevent, diagnose, and treat fatty liver disease and its complications.

Graduate Studentship Award

Designated Alberta Grant

Rachelle Davis, University of Calgary
Supervisor: Dr. Craig Jenne

Project Title: Assessing the efficacy of hepatitis B vaccination in the context of non-alcoholic fatty liver disease.

Non-alcoholic liver disease (NAFLD) is quickly becoming the most common cause of liver scarring, in part due to poor diet and sedentary lifestyle. As the obesity rates in Canada approach 50%, more information on how NAFLD affects the immune response is crucial. Patients with NAFLD are encouraged to receive a hepatitis B vaccine, however, it is currently not known how effective this vaccination, or the immune response to viral hepatitis would be in the context of fatty liver disease. Using advanced microscopy, Dr. Jenne’s team will study animal liver models to visualize how fatty liver responds to virus, and whether vaccines can adequately protect a patient with fatty liver disease. Results of this research may lead to changes in both vaccination policy and guidelines in order to better protect patients with NAFLD.

Summer Studentship Awards

Unrestricted Hepatobiliary Research Grant

Sarah Lépine, University of Alberta
Supervisor: Dr. Massimiliano Paganelli

Project Title: Characterization of human hepatoblasts during differentiation from definitive endoderm to hepatocytes using a pluripotent stem cell-derived 3D model of liver development.

What we know about liver development in embryos is mostly based on studies conducted on rodents. Currently available models using human cells are not representative of the complexity of the human liver. Using human stem cells, Dr. Paganelli’s team is able to generate 3D liver models composed of different cell types involved in liver development. In this project, the student will use one such 3D model to identify genes involved in the development of different types of liver cells. The results of this research will allow to finally validate current hypothesis on human liver development.

Designated Ontario Grant (sponsored by Ontario Association of Gastroenterology)

Kanwar Sahdra, University of Toronto
Supervisor: Dr. Jordan Feld

Project Title: Determination of the optimal vaccination strategy for hepatitis B.

Hepatitis B virus (HBV) infection is a major global public health problem with over 240 million people infected worldwide. The most common ways hepatitis B is spread are from mother to child at the time of birth and through sexual contact. Fortunately there is a highly effective vaccine that provides life-long protection from infection. Most countries vaccinate children at birth, including many provinces in Canada. In Ontario, children are vaccinated in grade 7 with the goal of preventing sexual transmission. Dr. Feld’s research will use an established model of HBV infection to determine which vaccination strategy (childhood or adolescent) is more cost-effective for Ontario. The results will be helpful to guide policy makers in Canada on the optimal vaccination strategy for this major public health issue.

Designated Hepatic Encephalopathy Grant

Charlène Blanchette, Université de Montréal
Supervisor: Dr. Chantal Bémeur

Project Title: Impact of exercise on brain protection in experimental chronic liver disease.

Liver disease may affect 1 in 4 Canadians and ranks 5^th among the causes of death. Loss of muscle mass and malnutrition are the most frequent complications of chronic liver disease (CLD) and cirrhosis. Hepatic encephalopathy (HE) is another serious complication of cirrhosis which could be a consequence of muscle mass loss. The Bémeur’s research team will investigate the impact of exercise on the prevention of muscle mass loss and HE in animal models. The results of this project will shed light on why severe complications such as HE develop in people with cirrhosis and may lead to the development of interventions that may improve the quality of life of the growing number of people suffering from liver disease.