CLF Research Grant Recipients
2016 Research Grants Competition Results
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 Kim
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.
Recipients 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.
Recipients of 2016 Summer Studentship Awards
Designated Alberta Grants
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.
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.
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 with the 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 development of new treatments for PBC.
Designated Ontario Grants
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.
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
Supervisor: 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.
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 are involved 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. Persisent neurological 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.
2015 CLF Research Grant Recipients
Recipients of 2015 Operating Grant Awards
Dr. Marc Bilodeau
Université de Montréal
Project Title: Role of extracellular matrix from cirrhotic livers in hepatocarcinogenesis
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and currently ranks third in cancer-related deaths. HCC is on the rise in North America as a result of the increasing prevalence of chronic hepatitis C and fatty liver disease. Scarring of the liver (fibrosis) is the result of all chronic liver diseases and is strongly associated with liver cancer. 90% of HCC occur in patients who have cirrhosis. The goal of Dr. Bilodeau’s research is to better understand the role of fibrosis in the development of liver cancer. For this purpose, Dr. Bilodeau will develop a model that can show the changes that occur in the liver during fibrosis. This model will allow him to study how different components of fibrosis promote the development and the resistance to treatment of liver cancer cells. This can help identify new approaches to treatment of liver cancer.
Dr. Binita Kamath
The Hospital for Sick Children
Co-applicant: Dr. Anand Ghanekar
Project Title: Biliary disease in a dish: modeling biliary disease using stem-cell derived cholangiocytes
A novel technology exists which allows us to derive stem cells from a tiny skin sample from a patient. These stem cells can develop into any cell type and are unique to the patient. Using these cells researchers can develop a patient-specific cell model in order to understand their disease and test new personalized therapies. This has been successful with heart and liver cells and Dr. Kamath plans to extend this novel technology to create bile duct cells. Bile duct disorders represent a significant disease burden. One such disease is biliary atresia and is the number one cause of liver transplantation in children. Another disease, primary sclerosing cholangitis (PSC) affects both children and adults with no effective treatment. The study of these diseases has been limited so far. Dr. Kamath and her team will develop laboratory-based patient-derived models of biliary disease that will allow them to understand disease mechanisms and test new therapies. The results of this research may lead to a reduced need for liver transplantation.
Dr. Andrew Mason
University of Alberta
Co-applicant: Dr. Michael Houghton
Project Title: Prevalence studies of human betaretrovirus infection in patients with liver disease
Patients with primary biliary cirrhosis (PBC) develop advanced liver disease. The cause of PBC is not known but the disease is thought to occur as a result of an infection in individuals who may have a predisposition to develop it. Dr. Mason’s laboratory has found evidence of virus infection in patients with PBC. They have isolated the virus in culture to provide proof that patients are truly infected with the virus. In the clinic, Dr. Mason found that PBC patients who had received a combination anti-retroviral therapy experienced significant improvement in their liver disease. This provides some circumstantial evidence that a retrovirus is responsible for this disease. With this research, Dr. Mason and his team are hoping to develop diagnostic tools to detect viral infection and monitor response to antiviral treatment.
Designated Ontario Liver Cancer Grant
Dr. Sean Cleary
University of Toronto
Co-applicants: Drs. Anand Ghanekar, Trevor Pugh
Project Title: Comprehensive evaluation of somatic alterations in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. Worldwide, HCC is the fifth most common cancer and the third most common cause of cancer death. Despite an overall declining incidence in most cancers, HCC is the second fastest growing cancer in Canada with a 40%-50% increase in incidence and mortality over the last 10 years. Currently, decisions regarding liver cancer treatment are made based on tumour characteristics, its size and number of lesions. Dr. Cleary’s research team has shown that genetic mutations in liver cancer have significant ability to predict how the tumour can be treated, risk of recurrence and survival of patients. This research will study the changes in DNA (genetic material) that can lead to liver cancer. This will provide unique insights into liver cancer, its causes and new, more effective treatments.
Designated Hepatitis C Grant
Dr. Jordan Feld
University of Toronto
Co-applicants: Drs. Markus Selzner, Nazia Selzner
Project Title: miRNA 122 inhibition during ex-vivo liver perfusion to prevent hepatitis C reinfection after liver transplantation
Hepatitis C virus (HCV) is a major cause of liver disease and liver cancer and is the leading reason for liver transplantation in Canada. HCV always re-infects the new liver after transplantation. Dr. Feld’s goal is to make the new liver impossible to re-infect. HCV uses a small RNA (genetic material) in liver cells called microRNA 122 (miR 122) for its lifecycle. Miravirsen is a medication that prevents the hepatitis C virus from reproducing itself. Dr. Feld and his research team will deliver miravirsen to donor livers through a novel system that keeps the liver oxygenated outside of the body before transplantation. Miravirsen will destroy miR 122 in the donor liver, making it impossible for the hepatitis C virus to re-infect when the liver is transplanted into an HCV-infected person. This research will lead to a cure of hepatitis C infection in liver transplant recipients.
Recipients of 2015 Summer Studentship Awards
Designated British Columbia Grants
Domnick Singh Manhas
(University of Northern British Columbia)
Supervisor: Dr. Paul Winwood
Project Title: The role of perlecan in hepatic fibrosis
In liver fibrosis (scarring of the liver), cells called hepatic stellate cells (HSCs) form and create deposits that lead to the development of scar tissue. Perlecans are proteins which are involved in many cell signaling processes including promoting a growth factor activity and thus stimulate growth and re-generation of liver cells. Data from Dr. Winwood’s lab indicate that perlecan proteins are increased in liver fibrosis. This research project will investigate the roles this protein plays in a mouse model of liver fibrosis. The results of this research may lead to the development of treatments for liver fibrosis and cirrhosis.
(University of British Columbia)
Supervisors: Drs. Orlee Guttman and Richard Schreiber
Project Title: The assessment of liver fibrosis in pediatric cystic fibrosis patients
Cystic fibrosis (CF) is the most common potentially fatal genetic condition affecting 1 in 2,500 live births. CF-associated liver disease (CFLD) occurs in 30% of CF patients. In 90% of cases, CFLD develops by age 18 and it is the third leading cause of death in CF patients. Diagnosis and monitoring of CFLD is challenging because specific tests for early detection of fibrosis in pediatric CFLD patients have not been identified. This pilot study aims to evaluate novel techniques for diagnosis and monitoring pediatric CFLD. All CF patients at BC Children’s Hospital will undergo ultrasound, MRI and novel tests for liver fibrosis including transient elastography (Fibroscan) and blood tests. Those with CFLD will have liver biopsy. This pilot study will inform on new tests for pediatric CFLD, and the results will be the basis for a larger Canadian study of pediatric CFLD fibrosis.
Designated Atlantic Canada Grant
Supervisor: Dr. Ian Alwayn
Project Title: In vivo hepatoprotection from ischemia-reperfusion injury (IRI) using a cell penetrating heme oxygenase protein
In an attempt to increase the number of donor organs available for transplantation, extended criteria donor (ECD) organs are more frequently considered. Unfortunately, ECD organs are more susceptible to injury in the absence of blood supply (due to lack of oxygen). Several methods have been described that may reduce the cellular injury in experimental models. One of the proteins that have shown promise in prolonging the life of donated organs is heme-oxygenase-1(HO-1). This project aims to determine the liver protective effect of this protein against ischemia reperfusion injury (IRI). IRI is the tissue damage caused when blood supply returns to the tissue after a period without oxygen. The ability to protect livers from IRI offers a new potential therapy that can be used to increase the success of liver transplantation. This may also have long-term beneficial effects in both acute and chronic rejection after a liver transplant.