Year: 2011

Balancing immunity and inflammation in the intestine

The human gut is a unique environment, simultaneously tolerating an endless variety of food particles and billions of helpful bacteria while retaining the ability to recognize and respond to potentially dangerous infectious diseases. In the developing world, gut infections such as cholera, amoebic dysentery, and parasitic worms are the leading causes of disease and death and are a major burden on development. Gut inflammation is also involved in inflammatory bowel disease and colorectal cancer. More than 200,000 Canadians suffer from inflammatory bowel disease (one of the world's highest incidence rates) and each year more than 22,000 Canadians will be diagnosed with colorectal cancer.

Dr. Colby Zaph studies mouse models of intestinal infection and inflammation in the gut in order to identify and understand the molecules and cells that regulate the balance between immunity and inflammation. His unique approach is to study the immune responses that develop after the gut is infected with a worm parasite called whipworm (Trichuris), which infects more than 800 million people globally.

Dr. Zaph hopes that his work will aid in understanding how the body knows it is infected (sensing), how it kills the invading organisms (inflammation), and how it turns off the response to stop inflammatory diseases from developing (resolution). The results from his research will hopefully identify pathways and targets that can both promote protective immune responses and eliminate inflammatory diseases of the intestine, including infectious diseases, inflammatory bowel diseases, and colorectal cancer.

Investigating the structure and function of the PIKK family of protein kinase

Many major chronic diseases, including cancer, Type 2 diabetes, and neurodegenerative disorders, are caused by perturbations in the internal communication network of the cells within the body. Signaling molecules, which are an important part of the intracellular communication network, coordinate different processes by relaying signals to switch on or off the proper sets of cellular machineries at the appropriate time. By understanding how these signaling molecules work, scientists hope to understand the molecular basis of different diseases and how to treat and prevent these diseases.

One important group of signaling molecules are the PIKK kinases. PIKK kinases are responsible for regulating cell growth and initiating responses to DNA damage, processes that are often disrupted or exploited in cancer formation and progression. Although recent research has identified the different proteins and protein complexes that PIKK kinases receive signals from or transmit signals to, exactly how these communication events occur at the molecular level remains poorly defined.

Dr. Calvin Yip's research program aims to understand the role of PIKK kinases in cancer progression. He is characterizing the three-dimensional structural and biochemical details of these molecules using an advanced imaging technique known as single-particle electron microscopy. Dr. Yip has obtained the first information on the 3D shape of a signaling complex formed by TOR, a member of the PIKK kinase family. With this foundation, he will use an interdisciplinary approach to combine cutting-edge electron microscopy technology and other biochemical and molecular biology methods to further determine how the TOR signaling complex receives and integrates information and how it sends signals to its targets.

Dr. Yip hopes that by focusing on how TOR and other PIKK signaling molecules carry out their biological activities, he will gain a deeper understanding of the fundamental processes of cell growth regulation. This will help pave the way for the development of new therapeutic approaches against cancer.

Treatment of drug-resistant influenza: Rationally designed inhibitors of viral neuraminidase

Each year the influenza virus infects approximately 10% of the human population, resulting in hundreds of thousands of deaths. Even in North America, nearly 40,000 annual “excess deaths” are attributed to influenza or to secondary bacterial infections. Despite a World Health Organization-monitored vaccine program, the disease remains a significant global health issue, requiring the use of antiviral drugs like oseltamivir (Tamiflu). A significant problem in controlling the spread of influenza is the emergence of oseltamivir-resistant strains.

To address this problem, Dr. Jeremy Wulff is taking a collaborative approach to develop potent new influenza virus inhibitors. With Professor Martin Boulanger's group at the University of Victoria Department of Biochemistry, Dr. Wulff has developed a new class of antiviral agents that function by a similar mechanism to oseltamivir. His research group is working to further improve the efficacy of these agents through structural and kinetic means. Finally, Dr. Wulff will test the potency of the new anti-influenza compounds in collaboration with Dr. Terrence Tumpey, from the U.S. Centers for Disease Control in Atlanta.

Identifying and developing new drugs to fight oseltamivir-resistant influenza is anticipated to have wide-reaching impacts on global health. In addition to creation of new influenza drugs, Dr. Wulff’s research interests include the development of novel methodologies for the synthesis of complex molecules, and the invention of new kinds of inhibitors that specifically block interactions between certain proteins involved in pancreatic cancer and HIV.

Melanoma and neurofibromatosis: genetic diseases linked by dark skinned mouse mutants

Melanoma is the most dangerous type of skin cancer. The incidence and rate of death from melanoma is rising in Canada. Since 1988, the death rate from melanoma increased 41% in men and 23% in women, which is the highest rate of increase for any type of cancer. Melanoma is primarily caused by repeated sun damage, which leads to the accumulation of mutations in the genes that regulate the survival and growth of pigment cells in the skin. The disease has a molecular basis, so it only makes sense that a molecular approach is being taken to find new therapies to treat this deadly disease. Dr. Catherine Van Raamsdonk is taking a unique molecular approach to identify genes that may be involved in melanoma. By studying three mouse strains that have a darker dermis (the lower-most layer of the skin), Dr. Van Raamsdonk and her colleagues have discovered three genes named GNAQ, GNA11 and NF1 that are important for pigment cell growth and survival. By studying how these genes interact with each other and how they are regulated at different stages of development, she hopes to understand how they may contribute to melanoma. This work will help to reveal the molecular basis of melanoma as well as other cancers. For example, the NF1 gene is also mutated in human neurofibromatosis, a genetic disease in which patients develop disfiguring tumors and hyper-pigmentation of the skin. Dr. Van Raamsdonk and her colleagues have also discovered that GNAQ and GNA11 are mutated in 78% of human uveal melanomas, the most common type of eye cancer. This breakthrough is significant because the mutations associated with uveal melanoma were previously unknown. Dr. Van Raamsdonk is the only professor in the world examining the role of GNAQ and GNA11 in mouse pigment cells, making this work unique and essential. The information she gains may be used to prevent, diagnose, and treat different types of cancers, including melanomas.

Childhood lung diseases: Infectious and inflammatory mechanisms

Lungs are for life. Unfortunately, the most frequent long-term illnesses in children and babies are respiratory system conditions. Children's lungs can be damaged in many ways: bacterial and viral infections, asthma, or faulty genes causing thick mucus to accumulate in the lungs of children with cystic fibrosis. Even the oxygen and artificial ventilation needed to sustain the lives of premature babies can cause lasting lung damage. A feature shared by all these serious childhood lung diseases is that some of the damage is caused by activation of the innate immune system, which is an important part of our immune defense network. The innate immune system is like a “double-edged” sword. While innate immunity is essential for keeping us healthy, it can cause excessive lung-damaging inflammation if the activity is not carefully controlled.

To prevent lung damage, Dr. Stuart Turvey is examining the systems that control the activity of the innate immune system. These control elements are known as negative regulators. His team will study these negative regulators in a variety of childhood lung diseases spanning premature babies and lung infections through to asthma and cystic fibrosis. The unique aspect of this project, and of Dr. Turvey's group in general, is a commitment to translational research focused on people with lung disease. This means research results from the lab bench are applied directly to patient care.

Rather than relying exclusively on laboratory (animal or cell) models of disease, Dr. Turvey’s team plans to examine genetic material donated by people affected by infectious and inflammatory lung diseases. The results of this work will be an exciting starting point for gaining a better understanding of the causes of childhood lung diseases and developing new medicines to safely control the damaging inflammation that occurs in the lungs of so many babies and children.

OCD translational multi-modal research program

According to the World Health Organization, obsessive-compulsive disorder (OCD) is one of the top 10 causes of disability. The disorder often begins in childhood and interferes with normal development. This disabling mental illness affects approximately 2 – 3 percent of British Columbians and, although treatable, is often under diagnosed.

The aim of Dr. S. Evelyn Stewart's research program is to improve the lives of BC children and families living with OCD. Her goal is to improve the evaluation and awareness of pediatric OCD in BC by conducting research to guide scientific and clinical understanding of OCD and its management by health professionals, and by establishing national and international linkages, which will lead to future research collaborations. Dr. Stewart's specific objectives for the first five years are to 1) create a unique research program within the new pediatric OCD clinic at BC Children's Hospital that is closely tied with the community, 2) establish a pediatric OCD DNA and research data site for BC, 3) launch a comprehensive patient-assessment method, and 4) investigate the outcomes and effectiveness of the program itself.

This program is unique, as it pulls together expertise from the clinic, the community and the laboratory. One important feature of Dr. Stewart's program is the effective transfer of new information between the clinic and the research lab in order to help the outcomes of practice inform research. Dr. Stewart anticipates this program will help limit the suffering and health-care costs related to OCD. The program is anticipated to develop into the first North American OCD Centre of Excellence.