To date, the only successful approach for curing type 1 diabetes is to replace the insulin-producing beta cells that have been destroyed by the disease. Pancreas- and islet-cell transplantation are promising therapeutic strategies; however, scarcity of transplantable tissue has limited their widespread use. One way to produce enough beta cells to cure type 1 diabetes is to determine how the cells develop normally within the embryo and apply this knowledge to the regeneration of beta cells in the culture dish or directly in people with diabetes.
Using human and mouse model systems, Dr. Francis Lynn’s research aims to enhance our understanding of normal regulatory pathways that govern pancreas- and insulin-producing pancreatic beta cell genesis and function. The hope is that a greater understanding will enable cell-based approaches for treating and curing diabetes. Lynn’s long-term objective is to understand how regulatory DNA-binding proteins called transcription factors drive beta cell formation and function. This research specifically focuses on one member of the Sox gene family of transcription factors named Sox4. Preliminary data suggest that Sox4 is instrumental in governing both the birth of beta cells and their replication later in life. These observations place Sox4 as a novel and previously unappreciated key regulator of beta cell biology.
Lynn hopes that a thorough characterization of the pathways through which Sox4 regulates beta cell formation and function will inform novel approaches for generation of large numbers of functional beta cells from human embryonic stem cells or induced pluripotent stem cells.
Existing viral vaccines provide immunity against a number of important infectious diseases. The technologies used to develop these vaccines generally work best against viruses that do not mutate very much in nature. However, conventional vaccine design approaches have proven inadequate for viruses such as HIV-1 that continuously evolve in order to evade our immune defenses. Thus, new vaccine design strategies are needed to tackle viruses like HIV.
Dr. Ralph Pantophlet’s research program is developing novel strategies for the design of vaccines that will induce broad immunity to HIV infection. Specifically, Pantophlet seeks to better understand molecular and immunological conditions that impact the elicitation of antibodies with the capacity to block the infectivity of a wide variety of HIV strains. This research focuses on these types of antibodies, dubbed “broadly neutralizing antibodies,” because of their demonstrable ability to block HIV infection in animal models. Another component of this program of research will be systematic studies to define neutralizing antibody target sites on HIV and investigate exposure of these sites at the molecular level. As part of the proposed research program, knowledge gained from the studies outlined above will be incorporated into the design of formulations to elicit target site-specific broadly neutralizing antibodies upon immunization. Thus, insight gained from this work is expected to advance HIV vaccine design efforts and be of significant interest to the field.
Although the focus will be on HIV, knowledge gained from this work may be applicable to other viruses for which conventional vaccine design approaches are also not optimal. Examples include hepatitis C virus, which like HIV is highly mutable and for which a vaccine has yet to be developed, and influenza, for which better vaccines are urgently being sought due to the constant threat of the emergence of a pandemic strain.
Keywords: HIV, vaccine, neutralizing antibody, immunogen design, vaccine immunology, B cell epitope, adjuvant, glycoprotein, T cell epitope, animal model
Dr. Laura Sly’s research program aims to improve our understanding of inflammatory bowel disease pathology and to identify and validate novel therapeutic approaches that will improve patient care. Her team has been investigating the role of SH2-containing Inositol Phosphatase (SHIP) in intestinal inflammation. SHIP is a protein that regulates enzymes involved in immune cell signaling. Sly’s research has shown that SHIP-deficient macrophages are hyper-responsive to IL-4, which drives them to an alternatively activated or M2 phenotype.
Using mice as a genetic model of M2 macrophages, Sly reported that M2 macrophages are protective against induced intestinal inflammation. Since then, her team has characterized a complimentary genetic model of M1-polarized macrophages and has identified key anti-inflammatory mediators that may be responsible for protection. Future investigations will focus on whether adoptive transfer of polarized macrophages or targeting macrophage polarization in situ can reduce intestinal inflammation in pre-clinical models of inflammatory bowel diseases.
Sly’s team has also developed a new mouse model of intestinal inflammation that shares key pathological features with Crohn’s disease. They have reported that SHIP-deficient mice develop spontaneous, discontinuous ileal inflammation accompanied by excessive collagen deposition and muscle thickening. Current research goals include targeting macrophage polarization or polarized macrophage products to reduce intestinal inflammation in pre-clinical models of inflammatory bowel disease, and identifying cell types and biochemical mechanisms that contribute to intestinal inflammation in SHIP-deficient mice. Together, these studies will identify cellular and biochemical targets and investigate new immunotherapeutic approaches that may useful in reducing intestinal inflammation in people with inflammatory bowel diseases.
Medical advances have played a fundamental role in dramatically increasing life expectancy in Canada and around the world. This has created challenges for the health-care system as a number of diseases exhibit increased incidence with age. Two examples include Alzheimer’s disease (AD) and cancer; cancer is now the leading cause of death in Canada. Continued research into the causes and progression of the disease is sure to provide advances in our ability to treat and eventually prevent the disease, with great benefit to our society and economy. The overall goal of Dr. Tim Storr’s biomedical research program is to develop new chemical tools to diagnose and treat the disease.
Storr’s team is focusing their research efforts in two areas: metal-overload diseases, and cancer. Many metal ions are essential to our existence, yet under certain conditions can become toxic. The team is currently studying the role of excess metal ions in the development of AD and Wilson’s disease (WD). The increased incidence of AD, and the lack of effective treatment strategies, underscores the pressing need for research into the causes, and the development of new therapeutic options. Storr’s team is investigating a new approach to AD treatment in which drug molecules are activated in the presence of excess metal ions, allowing for selective therapy. At the same time they are applying this treatment strategy to WD, a genetic metal overload disease in which excess metal ions accumulate in the liver. The overall goal is to bring forward new treatments for metal overload diseases that are generated at the site of need and only when excess metal ions are present.
Storr’s team is also applying chemical tools to cancer by developing imaging agents that allow for the early detection of the disease, and the ability to monitor treatment regimens. This information is key to a successful patient outcome, and the group is currently investigating differences in the energy needs of normal and cancerous tissue. Working at the interface of chemistry, biology, and medicine, this research promotes investigation across disciplines towards the design and testing of innovative disease treatments.
Pathogenic bacteria, such as P. aeruginosa, E. coli, and K. pneumonia, can cause serious infectious diseases such as pneumonia, urinary tract infections, and diarrhea. These bacteria are becoming resistant to many of our commonly used antibiotics and have been spreading rapidly over the past decade. Antibiotic-resistant bacteria are a serious threat to Canadian and global health, and new strategies are needed to combat them.
Groups of enzymes called beta-lactamases confer antibiotic resistance to the bacteria by allowing them to destroy beta-lactam antibiotics such as penicillin. Moreover, ongoing changes in bacterial beta-lactamase genes in nature are producing more potent enzymes to destroy our newest antibiotics.
Dr. Nobuhiko Tokuriki’s research will study the ways that beta-lactamase enzymes change. His team will combine experiments in the laboratory to identify mechanisms of change with detailed studies of enzyme function so they can develop ways to block their activity. The information obtained in this research will ultimately be used to develop novel, persistent, and sustainable antibiotics and inhibitors against pathogenic bacteria.
Cancer deaths are driven by two key biological processes: metastasis and treatment resistance. Although these processes are extensively studied as unrelated occurrences, evidence of shared signaling networks suggests common genetic or adaptive events. These pathways will change a therapy-responsive tumour to a resistant and lethal tumour. This occurs in prostate cancer where strategies used to kill tumours induce adaptive responses promoting the emergence of treatment-resistant tumours prone to metastasize. There is limited study of linkages between metastasis and treatment resistance, and Dr. Amina Zoubeidi’s research program will address an important knowledge gap in our understanding of aggressive tumour behavior in prostate cancer. The hope is that this research will translate into novel therapeutic development for prostate and other human cancers.
Zoubeidi’s work will be facilitated by her recent development of novel cell lines and xenograft models of prostate cancer that are resistant to a new generation of the AR pathway inhibitor drugs MDV3100 and abiraterone. These drugs, while recently introduced as therapeutics for patients with castration-resistant prostate cancer, offer survival gains of only four months and promote MDV- or abi-resistance. Zoubeidi has observed that MDV-resistant tumours metastasize whereas the castration-resistant tumours from which they were derived are non-metastatic. These observations suggest that tumours acquire metastatic traits in parallel with drug resistance.
Zoubeidi’s research program will focus on identifying common molecular mechanisms that elicit both metastasis and resistance to this new generation of prostate cancer drugs. Because tumour invasion and resistance dictate treatment outcome, pathways identified with this approach will represent relevant targets that can be inhibited singularly or jointly as more effective therapy. The research program is organized under three themes: the role of sustained AR activation in these processes; mechanisms associated with acquired EMT and their abilities to elicit treatment resistance; and the emergence of cancer cell “stem-ness” as a common mechanism driving treatment resistance and metastasis.
Canada is an aging society, and the proportion of Canadians older than 65 is estimated to double within the next 10 years. It is well known that aging is associated with declining health, but there is also tremendous variability in aging outcomes. While physical activity can reduce the risk of many age-related diseases, such as cardiovascular disease and diabetes, Canadian seniors have low rates of physical activity.
Dr. Christiane Hoppmann’s research takes an innovative approach to examining key psychological factors, such as goals and planning, that may explain why some seniors are successful at implementing physical activity into their daily lives while others remain physically inactive. There is also recognition that the translation of physical activity goals into action demands cognitive and emotional resources that become increasingly limited with aging. For example, seniors with memory failures and fear of falling may encounter more difficulties engaging in physical activity. Hoppmann’s team will conduct an in-depth investigation of the psychological determinants of daily physical activity using a design called time-sampling. This method, which involves seniors completing a diary of their physical activities, memory, and emotions several times a day, will allow an examination of daily fluctuations across domains of functioning. Physical activity will also be assessed using portable electronic devices worn on the hip called accelerometers. Hoppmann’s team will also conduct one- and two-year follow-up assessments to link daily physical activity with long-term physical and mental health.
This research constitutes an important step to better understanding the psychological determinants of physical activity in seniors and their impact on physical and mental health. Findings will inform novel interventions (e.g. targeting goals and emotion-regulation) to promote healthy aging in community-dwelling and particularly vulnerable seniors in Canada.
Millions of newborns and infants die each year from infectious diseases. Many of these deaths are preventable, and analysis of the immune development of children can help define paths for medical intervention that may save lives.
Dr. Tobias Kollmann’s research team is conducting the first global comparison of immune development in cohorts of children from different countries. This project will compare the immune development of children born in Vancouver to those born in South Africa, Mozambique, Ecuador and Belgium. Preliminary research has found striking qualitative and quantitative differences in children’s immune development that appear to be directly related to their genetic make-up as well as the particular environment to which they are exposed. Kollmann’s team is dissecting the cause-effect relationship for the role of host genetics and studying the environmental factors that direct the developmental path of the innate and adaptive immune responses. Analysis of these genetic and environmental factors will potentially reveal pathways that direct future efforts to treat and prevent infectious diseases.
Kollmann’s team is already developing a platform that will help deliver targeted vaccinations to protect newborns. Using genetically altered strains of Listeria monocytogenes, the vaccine will induce a desired immune response only in specific cells and then disappear without harming the child. Preliminary data suggest this goal is within reach, and Kollmann’s team is working in partnership with industry to design and test a Listeria-based vaccination for newborns. Through this work, safe yet effective methods will be identified to prevent millions of newborn and infant deaths due to infectious diseases.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a syndrome marked by inattention and/or hyperactivity/impulsivity that affects 5-8 percent of Canadian youth. It makes up the most frequent referral for children’s mental health services and is associated with considerable psychosocial morbidity. A significant aspect of the impairment in ADHD is the difficulty these children face in getting along with peers. More than half of children with this condition are severely disliked by their peers or do not have a single friend. Peer problems result in loneliness and sadness for children with ADHD, and heighten the risk for future school failure, drug abuse, and delinquency. Treatments for the core symptoms of ADHD are ineffective at changing peers’ liking of children with ADHD, and if existing treatments do not also improve peer relationship problems, children with ADHD remain likely to experience poor health outcomes. These findings underscore the importance of developing adjunctive treatments capable of addressing the peer problems faced by children with ADHD.
Dr. Amori Mikami’s research focuses on the development, efficacy testing, and knowledge translation of novel psychosocial interventions for peer problems in children with ADHD. She proposes to expand upon an innovative intervention: training parents to improve the peer relationships of their children with ADHD. This is known as parental friendship coaching (PFC). Supported by the National Institute of Mental Health, Mikami created the PFC intervention and demonstrated in a randomized trial of 62 children with ADHD that PFC appeared effective relative to a no-treatment control group.
Mikami is following up on these promising preliminary results with a more definitive test of PFC and a better study of the mechanisms behind treatment efficacy. She will compare PFC against an active attention control intervention (to ensure the incremental value of the PFC techniques beyond social support and therapist time), involve 150 children from two diverse areas in Canada, follow up with participants eight months post-intervention, and use a thorough battery to measure outcomes, mediators, and moderators. Future studies will focus on disseminating new knowledge about PFC and peer problems to practitioners.
Malignant lymphomas are the fifth most frequent cancer in humans, affecting patients of all ages. Despite generally effective treatments, a significant number of patients still die from the progressive disease. Interactions of the malignant cells with cells of the tumor microenvironment are increasingly recognized to play a pivotal role in the development of many lymphoma subtypes. However, the clinical potential of an improved understanding of microenvironment-related biology remains largely untapped.
Dr. Christian Steidl’s research focuses on B-cell lymphomas; in particular on the two related subtypes — Hodgkin lymphoma and primary mediastinal B-cell lymphoma — that often affect adolescents and young adults. This study will investigate tumor microenvironment interactions as therapeutic targets in B-cell lymphomas. Steidl’s team will seek to elucidate the underlying pathobiology of the tumor microenvironment, and macrophage interactions in particular, to identify novel drug targets and pave the way for the design of innovative clinical trials.
The study will also identify outcome predictors and resistance mechanisms of childhood and adult Hodgkin lymphoma. Molecular treatment outcome predictors will be developed using genomics approaches. Better outcome prediction using biological markers will identify patients at high risk and allow for personalized treatment approaches for children and adults suffering from relapsed Hodgkin lymphoma. Specifically, the recent emergence of novel targeted therapies holds the promise to overcome this high risk using these therapies to augment or replace existing therapies.
Finally, this research will define the mutational landscape of Hodgkin lymphoma and primary mediastinal B-cell lymphoma. This will involve the complete characterization of mutations by next-generation sequencing approaches. Preliminary data indicate that somatic mutations in both diseases are critically deregulating molecular pathways that might be targetable by novel therapeutic approaches. These studies will aim to transform novel findings into meaningful advances in clinical hematology.
