Recent developments in imaging devices provide researchers with powerful tools to detect cancers and explore the impact of therapy on tumour cells. This research program plans to leverage the strengths of positron emission tomography combined to computed tomography (PET/CT) to characterize and rapidly assess response to therapy in 3 common cancers (breast, prostate, and lymphoma) and combine this information with other predictors of aggressiveness and treatment failure. PET/CT imaging is a powerful technique that combines the strenghts of a PET scanner (which can measure tumor receptors and metabolic activity) with those of a CT scanner (which provides detailed images of a patient’s anatomy). The combination of both approaches could rapidly identify patients that are likely to fail conventional therapy and offer them alternatives that are better suited to the nature of their cancer. The research program is designed around 3 core themes. The first research them focuses on the development of methods to predict the outcome of patients with breast cancer who are treated with chemotherapy or hormone therapy. We will pursue ongoing work to develop animal models of breast cancer and imaging methods to monitor response of these tumors to chemotherapy and hormone therapy. We will also conduct clincial studies to correlate the results of imaging studies performed with PET/CT with outcome and response to therapy. The second theme focuses on the development of new probes that target specific proteins that are overexpressed at the surface of breast and prostate tumors. These probes might eventually be translated into clinical studies as breast and prostate cancer diagnostic agents for use with PET/CT, or even for therapy by tagging them with radioisotopes that can destroy tumor cells by proximity. The last theme proposes practical research studies of immediate clinical interest. We will assess the accuracy of PET/CT imaging in staging prostate cancer (with 2 radiopharmaceuticals designed to assess tumor lipid synthesis and bone turnover). We will also extend to the Vancouver site an ongoing study that assesses PET/CT imaging to predict the early response to chemotherapy in large cell lymphoma.
Year: 2007
Carbohydrate recognition and metabolism in streptococcus pneumoniae: Structural and functional dissection of unique virulence factors
Pneumonia is an acute respiratory disease, the major cause of which is the bacterium Streptococcus pneumoniae. This bacterium is the leading cause of death from infectious disease in North America and a leading cause of death worldwide, particularly in children and the elderly. This bacterium can also cause meningitis, septicemia, and otitis media (middle ear infection). Reports indicate that 40 per cent of pneumonia cases caused by S. pneumoniae are resistant to penicillin and new multidrug resistant strains are beginning to emerge. To reduce increasing rates of antibiotic resistance and augment judicious use of the pneumococcal vaccine, alternative methods for treating S. pneumoniae infections must be found. Several proteins have been found in S. pneumoniae that are believed to contribute to its virulence. It is suspected some of these proteins destroy sugars such as glycogen in specific lung cells that normally serve to protect the lungs against infection. These damaging proteins are potential targets for preventing or slowing the infection. Dr. Alisdair Boraston will focus on two aspects of these S. pneumoniae proteins: if and how these proteins are destroying sugars and how to inhibit this activity. Biochemical studies will provide understanding about how these enzymes degrade sugars and whether any inhibitor molecules can interfere with this. Structural studies using X-ray crystallography will show structural features of the proteins that contribute to their activity and aid in the design of new inhibitors. Taken together, this information will lead to new approaches and agents to target pneumonia caused by S. pneumoniae.
Defining the structural basis of surface antigen glycoprotein mediated virulence in Toxoplasma gondii
Toxoplasmosis is a serious human pathogen carried by about one-third of the population. People develop toxoplasmosis either after ingesting undercooked meat that contains T. gondii cysts, or by coming into contact with cat feces from an infected animal. Once infected, healthy adults initially show a range of temporary flu-like symptoms; however, while these symptoms pass, the parasite Toxoplasma gondii remains in the body for life, with limited drug treatment available. Infection during pregnancy can cause miscarriage, neonatal death and a variety of fetal abnormalities, including developmental delays. It is also harmful to those whose immune systems are compromised, such as those with HIV/AIDS, cancer or who have had an organ transplant. Very little is known about how T. gondii causes disease. Dr. Martin Boulanger is studying the structure of host-pathogen interactions to determine the activities that allow T. gondii to attach to and invade human cells. With this information, treatments can be developed to prevent or manage Toxoplasmosis. This work will also apply to better understanding of other parasite-caused disease such as malaria and cryptosporidiosis.
Development and application of data standards for flow cytometry
Flow cytometry is a method of identifying and sorting cells and their components by staining with a fluorescent dye and detecting the resulting fluorescence (usually by laser beam illumination). Flow cytometry is widely used in health research (e.g. for stem cell identification and vaccine development), and in the diagnosis, monitoring and treatment of a variety of diseases, including cancers and HIV/AIDS.
Recent advances in high-throughput flow cytometry allows for the analysis of thousands of samples per day, creating detailed descriptions about millions of individual cells. Managing and analyzing this volume of data is a challenge that Dr. Ryan Brinkman is addressing through the development of data standards, algorithms, and bioinformatics tools. Dr. Brinkman is also applying these methodologies to the analysis of several large clinical flow cytometry datasets in an effort to identify biomarkers for lymphoma, neonatal auto-immunity, and graft versus host disease.
Pathogen bioinformatics and the evolution of microbial virulence
Infectious diseases are responsible for roughly a third of annual deaths worldwide and contribute greatly to productivity loss. Antimicrobial resistance and newly emerging diseases are both cause for significant concern. With the advent of microbial whole-genome sequencing, there has been renewed optimism that computational analyses of microbial genomes will allow for faster identification of promising new therapeutic targets, which can then be further investigated with laboratory studies. At the moment, however, current computational practices are not accurate enough to be truly effective. Dr. Fiona Brinkman is interested in improving computational methods used to identify new potential bacterial vaccine components or drug/diagnostic targets. She is focusing in particular on improving identification methods for two regions: bacterial cell surface and secreted proteins, since they are the most accessible targets; and clusters of genes called genomic islands, which appear to disproportionately contain virulence genes and so could aid investigations of bacterial pathogenicity. Her research group is also studying the evolution of microbial virulence, both from the pathogen and host perspective, using bioinformatic approaches supported by laboratory studies. This work aims to develop methods and insights that may accelerate the identification of promising new targets from pathogen genomes. With the ability to analyze multiple infectious disease-causing microbes in parallel, this research has the potential to have a wide reaching impact on efforts to control multiple infectious diseases.
Population-Based Genetic Studies of Cancer and Healthy Aging
The number of elderly Canadians is increasing as the baby boomers age. Insight into how to promote healthy aging, coupled with advice that can be provided to our population as it ages, will influence Canada’s healthcare costs, as well as the quality of life of a large segment of our population. Cancer and aging are intimately connected. Cancer incidence rises with age, and this increase accelerates dramatically over 60 years of age. Cancer and other aging-associated diseases like cardiovascular disease are thought to result from the interaction of numerous genetic and environmental or lifestyle factors. Population-based studies that use large groups of affected and unaffected individuals are now the preferred method to study the genetics of complex diseases. This program has clinical relevance and involves close collaboration with clinical experts to study healthy aging and two specific cancers, non-Hodgkin lymphoma and cervical cancer. The overall objective is to discover genetic factors that contribute to susceptibility to cancer or confer long-term good health. The program will use state-of-the-art genetic analysis methods, and over the next 5 years will expand these projects and add additional types of cancer. This coordinated study of cancer and healthy aging is a unique and innovative approach by which we will increase our understanding of the connection between cancer and aging and benefit from new knowledge regarding the basis of common aging-associated diseases like cancer. This research will lead to development of clinically useful markers that will help individuals avoid developing diseases as they age.
Neighborhood Social Capital and Population Health: Exploring Community Resources and Access
Recently, the concept of community social capital – the extent and quality of community social ties – is receiving a great deal of interest from population health researchers and policymakers. This interest stems from efforts to understand relationships between the social and economic conditions of communities and the health and well-being of the people who live in these communities. Research on social capital to date has been focused primarily on the extent of social ties and interpersonal trust in communities. This limited focus has overlooked crucial elements that make community social ties useful for maintaining or improving population health: the various socioeconomic, political, and psychosocial resources that are possessed by members of social networks and how residents access (or are restricted from accessing) these network-based resources.
Dr. Richard Carpiano is determining how specific resources based in neighbourhood social ties, and access to these resources, matter for adult health and well-being. He will analyze one of the best available community health datasets for investigating social capital and neighborhood socioeconomic conditions: the Los Angeles Family and Neighborhood Survey (L.A.FANS). This project has two major benefits. It will extend population health planners’ understanding of community social capital by showing what aspects of neighbourhood social ties matter for health and well-being and how social conditions of local areas have health promoting and health damaging consequences. More broadly, it will help extend population health research on neighbourhoods and local communities by exploring the different ways that social context matters for adult health and well-being.
Toxicology of Natural Products and Synthetic Drugs
Adverse drug reactions are a major health risk that contributes to increasing health care costs and strain on the system. They are the sixth leading cause of death in the United States, and statistics indicate that the situation would be similar in Canada. There are many types of adverse drug reactions. Liver toxicity (poisoning) leading to fatal liver failure is one of the most common. In most cases, the mechanisms that cause drug induced liver toxicity are not well-known and even less is known about the effects of natural products (herbal products or dietary supplements) on liver function. With the ever increasing demand of herbal products by consumers, there is an urgent need to conduct detailed and systematic scientific investigations on their hepatic metabolic effects. Dr. Chang’s work is aimed at characterizing the effect of natural products and synthetic drugs on liver function and determining how they are able to give rise to damage in liver cells. A better understanding of the mechanisms will contribute to a safer and more rational use of natural/herbal products and synthetic drugs.
Transcriptional regulation of genes in health and disease
The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.
Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.
Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.
Novel Antimicrobial Surface Coatings for Urologic Devices
Health Issue:Urinary catheters provide drainage of the bladder to an external collecting device and are the most commonly placed medical devices. Ureteral stents provide drainage of urine from the kidney to the bladder and are used in the treatment of kidney stones. Both of these devices are foreign bodies in the urinary tract and allow bacteria to adhere and result in urinary tract infections and encrustations leading to device blockage and malfunction. Catheter and ureteral stent-associated infections prolong hospital stay, result in greater health care costs and may result in blood-borne bacterial infections possibly resulting in death. Antibiotics may be given for the duration that the drainage devices remain in the body, but there is great concern that the overuse of antibiotics will lead to the development of antibiotic resistant bacteria, or superbugs. Novel ways to reduce catheter and stent related infections would certainly improve patient care and decrease costs to the health care system without inducing resistant superbugs. Project Objective: To develop and test a novel peptide (protein) coating on urinary devices to reduce device-related urinary tract infection. Work to Undertake: Urinary catheters and stents will be coated with this novel peptide and evaluated for their ability to resist infection and encrustation using test tubes, bacterial cultures, and animals. Ultimately, human trials will be required. Unique to this research program/proposal of research: This novel peptide coating was discovered at the University of British Columbia by two researchers and is already being applied to artificial joints and implants used in orthopaedics. This will be the first use of this novel, promising technique in protecting urologic devices from infection and encrustation.