2017 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 5th 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.
2016 Research Grant Competition Results
Team Grant in Hepatocellular Carcinoma
Dr. Ian McGilvray, University Health Network, University of Toronto
Co-Applicants: Drs. Warren Chan, Thomas Michalak, Markus Selzner, Sean Cleary, Jennifer Knox
Matching Funds Provided by Toronto General & Western Hospital Foundation
Project Title: Nanoparticle enhancement of host immunity to hepatocellular cancer
Primary liver cancer (cancer that develops from cells of the liver) is not only one of the fastest rising but also one of the deadliest forms of cancer in Canada. Due to late diagnosis and disease severity, more than half of all liver cancer patients cannot be effectively treated with current therapies. In partthis is because there are cells in the cancers that shield them from the body’s immune system. These cells are called tumour-associated macrophages (TAMs). If these cells could be targeted and destroyed, the cancers will be more vulnerable to being eliminated by the body’s immune system or by standard chemotherapy. Led by Dr. McGilvray, this multidisciplinary team will use nanotechnology to target and destroy TAMs. Nanotechnology uses tiny engineered particles (called nanoparticles) that can carry and deliver drugs. Using this technology, they hope to develop and test a new treatment option for patients diagnosed with liver cancer.
Recipient of 2016 Operating Grant Award
Dr. Hemant Shah, University Health Network, University of Toronto
Co-applicants: Drs. Len Kelly, Rachel Sacks-Davis, Davis Smookler, John Kir
Project Title: Increased testing in remote First Nations Communities to monitor HCV spread.
Hepatitis C virus (HCV) is one of the primary causes of death by infection in Canada, surpassing HIV as a cause of death since 2007. Effective cures are available; the challenge remains linkage of infected individuals with health care (testing and evaluation for treatment). There is no vaccine to prevent HCV. Treating hepatitis C in order to prevent spreading the disease among vulnerable populations may be the only way to eradicate the disease. This approach has been successful with HIV and tuberculosis, but has yet to be tested for hepatitis C. All evidence suggests that spread of HCV is greater in First Nations Communities, yet they have difficulty accessing health care. In this study, researchers will develop a model for dramatically increasing testing in remote First Nations communities by using a novel finger-prick test kit. Furthermore the data gathered will then be available for a future trial of treatment as prevention model.
Recipient of 2016 Graduate Studentship Awards
Designated “Taking Action Against PSC” Award
Dr. Amanda Ricciuto, The Hospital for Sick Children Toronto, Ontario
Supervisor: Dr. Binita Kamath
Project Title: Pediatric PSC-IBD: Optimizing colitis monitoring strategies to enhance liver disease outcomes.
In adults, PSC-IBD (inflammatory bowel disease co-occurring with PSC) seems to be a unique type of IBD, with extensive inflammation of the colon, but mild symptoms. People are increasingly recognizing the importance of healing the gut in PSC-IBD to improve liver disease. Little is known about PSC-IBD in children, although this population is particularly important because it offers the opportunity for early intervention. Given the mild symptoms in adult PSC-IBD, mere symptom control in pediatric PSC-IBD may be insufficient. More aggressive approach to healing of the bowel, guided by colonoscopy and other tests like stool samples, may be needed and may be associated with better outcomes for liver disease. The aims of this study are to describe the IBD in children with PSC-IBD and to define what symptoms and stool samples can be used to determine the severity of IBD in children with PSC-IBD, compared to a control group of children with IBD without liver disease.
Unrestricted Hepatobiliary Research Grants
Mr. Kaveh Farrokhi, University of Toronto
Supervisor: Dr. Gary Levy
Project Title: Inhibition of the FGL2-FcγRIIB/RIII immunosuppressive pathway restores antiviral innate and adaptive immunity during chronic viral infection.
Over 500 million people worldwide are chronically infected with hepatitis B or hepatitis C. Both diseases can lead to cirrhosis and liver cancer. Over 60% of liver cancer is associated with chronic hepatitis B and hepatitis C. Both HBV and HCV persist in the body by making your body produce proteins that prevent your immune system from fighting these two viruses. Dr. Levy’s laboratory has identified one such protein, which has been shown to be elevated in both HBV and HCV infections. This research project involves examining this protein as a potential target for the development of new treatment of chronic viral hepatitis.
Ms. Celeste Lavallee, University of Alberta
Supervisor: Dr. Justine Turner
Project Title: Mechanisms of neonatal intestinal failure liver disease: exploring the gut-liver axis.
Liver disease is a serious problem for babies born with short bowel syndrome (SBS). These babies often need liver transplants, but many die while waiting on transplant lists. Babies with SBS need to be fed intravenously. This is called parenteral nutrition (PN). To date, the only certain cure for their liver disease is to stop PN. But this cannot be done for babies who rely on PN to live and grow. We need other ways to threat their liver disease, and that will only come from better understanding what causes it. Most babies with SBS have lost part of their gut called the ileum. It is believed this changes their gut bacteria which is linked to liver damage. The research project will research new treatments for babies with SBS and their life-threatening liver disease.
Recipient of 2016 Summer Studentship Awards
Designated Alberta Grants
Nikolas Ewasechko, University of Calgary
Supervisor: Dr. Carla Coffin
Project Title: Assessment of baseline hepatitis B virus immunity and HBV vaccine responses in patients with non-alcoholic fatty liver disease.
Hepatitis B affects over 240 million people worldwide, including over 240,000 in Canada. Chronic hepatitis B can lead to liver scarring (cirrhosis), and liver cancer, thus making hepatitis B infection an urgent global health issue. As well, the obesity epidemic, sedentary lifestyle and high-fat diet have contributed to the emergence of non-alcoholic fatty liver disease (NAFLD) as another major cause of cirrhosis. While coexistence of hepatitis B and NAFLD are believed to hasten liver damage, the exact process by which this occurs is not known. In addition, while an effective vaccine exists for HBV, the effect of NAFLD on HBV vaccine efficacy is also unknown. With obesity on the rise, the goal of the research project is to address the need for research on the effect of NAFLD on HBV immunity by assessing immune responses to HBV in patients with NAFLD.
Amber Hager, University of Alberta
Supervisor: Drs. Diana Mager and Jason Yap
Project Title: Body composition in infants and children pre-and-post liver transplantation.
Malnutrition is very common in young infants and children with chronic liver disease awaiting liver transplantation. This is typically due to poor intake and malabsorption of important nutrients that are needed for growth and development. Although dietary intake and malabsorption may improve after liver transplantation, there is substantial evidence that infants and children may still experience delayed growth for several years after liver transplantation. One of the major reasons for this may be the need for lifelong use of immunosuppressive medications after liver transplantation. Very little is known about how body composition changes in infants and children after liver transplantation. Body composition (lean body mass and fat mass) will be studied using bone mineral density scans that are routinely done in infants and children with liver disease. Researchers will be able to measure both muscle and fat mass, in addition to weight and height and to measure the rates of growth in infants and children. This information will be used to develop clinical treatments to address delayed growth in infants and children after liver transplantation.
Emma Hjartarson, University of Alberta
Supervisor: Dr. Puneeta Tandon
Project Title: A prospective study in patients with cirrhosis to assess readiness for advanced care planning discussions (ACP)
The common end point for all liver diseases is cirrhosis, a condition in which the scarred liver is no longer responsive to treatment and continues to deteriorate ending in death. Liver transplantation is a life-saving option but has limited impact due to critical organ donor shortages across the country. A diagnosis of cirrhosis is not synonymous with advanced care planning (ACP) as the trajectory to death varies dramatically from months to years to decades. As such, it is not surprising that a pilot study found that many participants are reluctant to mention ACP let alone work with patients to develop goals of care. This is a major health care gap that can be informed by surveying patients with cirrhosis regarding their readiness for ACP, their understanding, and expectations. Outcomes from this prospective, multicenter study will be clinically relevant and will improve patient care.
Youngkee (Jake) Hong, University of Alberta
Supervisor: Dr. Andrew Mason
Project Title: T-lymphocyte proinflammatory responses to human betavirus peptides.
Dr. Mason’s laboratory has discovered a novel human betaretrovirus (HBRV) in patients with autoimmune liver disease primary biliary cholangitis (PBC). Studies have been focused on finding out whether the virus is involved withthe disease process. Using deep DNA sequencing methods, it has been found that the virus DNA inserts into the DNA of bile ducts. This occurs in about 75% of patients. Dr. Mason’s team has also found that combination anti-retroviral therapy results in diminished viral load which coincides with improvement of disease. This finding suggests that the virus plays a role in the development of PBC. The student will study immune responses to viral infection in PBC patients. The results of this study may lead to developmentof new treatments for PBC.
Designated Ontario Grants
Alexander Anagnostopoulos, McMaster University
Supervisor: Dr. Gregory Steinberg
Project Title: Unravelling the connections between obesity, NAFLD and metformin for the treatment of hepatocellular carcinoma
Liver cancer is one of the few types of cancer that affects more people today than it did 40 years ago. Diagnosis often occurs in the advanced stages of the disease leading to poor prognosis, with five-year survival rates of only 20%. Metformin is the most widely prescribed diabetes medication worldwide and there is evidence that it can reduce the risk of liver cancer development in patients with diabetes. The study will shed light on how metformin is able to reduce the risk of developing liver cancer and help physicians treat patients who are susceptible to this deadly disease.
Leah Burkovsky, University of Ottawa
Supervisor: Dr. Morgan Fullerton
Project Title: The regulation of cholesterol synthesis in non-alcoholic fatty liver disease
Obesity is now the most common cause of non-alcoholic fatty liver disease (NAFLD). It is now appreciated that the amount of cholesterol made in the liver is critical for the start and progression of the disease. The important metabolic protein (AMPK) regulates many parts of metabolism, including the production of cholesterol. This protein can also regulate the critical enzyme involved in the reduction of cholesterol. The same protein is also the target of the widely used cholesterol-lowering drugs (statins). However, although this type of regulation was identified more than 40 years ago, we still do not know its role or whether it affects how the medication functions. The objective of this research project is to determine the importance of AMPK in NAFLD, in the hopes of identifying new therapies to treat this disease, which at the moment has no cure.
Shirley (Xue) Jiang, Toronto General Hospital Research Institute
Supervisors: Dr. Harry Janssen
Project Title: Application of host DNA damage response by hepatitis B virus to establish chronic infection.
Chronic hepatitis B (CHB) cannot be cured and leads to liver cirrhosis and cancer. Hepatitis B virus (HBV) changes cellular mechanisms that can detect the presence of damaged genetic material, called DNA damage responses (DDR). Sufficient information for understanding this process is missing due to lack of proper experimental models. Researchers aim to use liver cells obtained from chronically infected patients and study them to understand how chronic hepatitis B develops. Researchers will infect liver cells with HBV and investigate the changes that happen in DDR. They will then block these changes to stop the infection. The goal of this research is to identify new therapies and find a cure for chronic hepatitis B.
Curtis Quan, University of Ottawa
Supervisor: Dr. John Pezacki
Project Title: The role of microRNA in the innate antiviral response and hepatitis C virus pathogenesis.
Liver cancer is one of the most common types of cancer and is diagnoses in more than half a million people worldwide. One of the leading causes of liver cancer is hepatitis C. Hepatitis C leads to cirrhosis, cancer and liver failure. The research project will explore how our body’s first line of defence, the innate immune system, responds to and restricts hepatitis C infection in hopes of understanding how this disease leads to liver cancer. In this project, the student will work on identifying microRNAs produced in the liver that areinvolved in the immune response to hepatitis C. The goal of the project is to develop novel hepatitis C therapies.
Designated Hepatic Encephalopathy Grant
Kim Phat Pham, University of Montreal
Supervisor: Dr. Christopher Rose
Project Title: The impact of recurrent episodes of overt hepatic encephalopathy on neuronal cell death in rats with chronic liver disease.
Hepatic encephalopathy (HE) is a complex condition and a major complication of chronic liver disease and cirrhosis. HE leads to confusion, lethargy, disorientation, and could eventually lead to coma. One study has shown that severe HE can lead to permanent brain damage. Persisentneurological complications were observed in up to 45% of patients following liver transplantation. The aim of this project is to study an HE animal model induced by ammonia in order to assess whether episodes of HE can lead to loss of brain function and behavioural changes in rats. Understanding episodes of HE is essential in order to find ways to prevent permanent brain damage in people awaiting liver transplantation.