Inflammatory bowel diseases (IBD) are chronic conditions characterized by severe inflammation of parts of the bowel, causing significant symptoms, such as diarrhea, pain and intestinal bleeding. There are two main types of IBD: Crohn’s disease and ulcerative colitis. IBD is prevalent in Canada, with an estimated 170,000 people suffering from the disease. Despite years of effort, the causes of these disorders remain incompletely and inadequately understood. The intestinal inflammation in IBD is thought to result from abnormal responses to the bacteria that live normally in the gut. In healthy individuals, the immune system is able to distinguish between harmless (commensal) bacteria and those that cause infections (pathogens). In IBD patients, the immune system elicits an aberrant and aggressive response against components of host commensal bacteria. Dendritic cells (DC) and regulatory T cells (nTreg) are two types of cells important in maintaining a healthy intestinal immune system. Defects in the development or function of these cells could ultimately lead to inappropriate responses to commensal bacteria, or certain commensal bacteria or pathogens could perturb the normal immune state of the gut. Dr. Gijs Hardenberg is investigating the interplay between host commensal bacteria and the immune system in IBD. He is studying the roles of nTreg and immune responses, focusing on the bacterial protein flagellin, which has been shown to be the major target of intestinal immune responses in Crohnâs disease patients. His work aims to understand how IBD begins and persists how it might ultimately be treated or even prevented. The findings from these studies may also be broadly applicable to other autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and lupus.
Research Location: Vancouver Coastal Health Research Institute
Healthcare workers and antineoplastic drugs: Identifying the determinants of exposure and current challenges to reducing exposure
In health care settings, antineoplastic drugs are prepared and administered daily, mainly for the treatment of cancer. These drugs are inherently toxic and can therefore affect normal, healthy cells. On-the-job (occupational) exposure to antineoplastic drugs has been shown to cause a variety of health effects including cell mutations, adverse developmental and reproductive outcomes, and cancer. Absorption through the skin is suspected to be the main route of occupational exposure to antineoplastic drugs, and in spite of control measures used during their handling and preparation, studies have found antineoplastic drug contamination of surfaces in health care facilities. However, few studies have examined the potential for occupational dermal exposure. Chun-Yip Hon previously conducted a pilot study assessing the occupational dermal exposure risks of antineoplastic drugs to healthcare workers, and evaluated the cleaning protocols for drug-contaminated surfaces. He found that antineoplastic drug contamination of the drug preparation area is likely in British Columbian hospital pharmacies even after cleaning, and that the hands of pharmacy personnel may be contaminated even if the worker was not responsible for preparing the drug products. Heâs now undertaking a full-scale study at hospitals situated within the Lower Mainland, investigating the procedures and process flows of antineoplastic drug handling, and determining who may come into contact with the drugs. He is quantifying antineoplastic drug contamination levels on surfaces throughout their process flow in each hospital, assessing workersâ knowledge of safe handling procedures as well as their risk of occupational dermal exposure. He will also determine the presence of antineoplastic drugs in health care workers through biological monitoring. Honâs findings will determine the risk factors associated with occupational exposure to antineoplastic drugs in the health care sector, providing key information for those who work with antineoplastic drugs, occupational health and safety professionals, risk managers and policy makers.
Measuring confidence with wheelchair mobility
In 2000/01, approximately 264 000 Canadians required a wheelchair for mobility. Independence with mobility is important for day-to-day living, social activities, and overall quality of life. However, although wheelchair skills training has become much more prevalent in the past decade, more than half of Canadians using a wheelchair are not independent and require assistance with their mobility. One factor that has not yet been explored by research is the impact of confidence on a personâs mobility and independence. Confidence contributes to the acquisition of knowledge and refinement of new abilities. It also influences an individualâs choice of activities, motivational level, effort, resilience, life choices, and perseverance in the face of difficulties. Preliminary research suggests that confidence may affect wheelchair mobility, but there is currently no tool to assess or address this important factor. Paula Rushton is developing and validating an assessment tool to measure wheelchair skills confidence. The creation of this tool involves input from occupational therapists, physical therapists and physicians, as well as wheelchair users in the community. The second phase of her project will involve testing the tool with one hundred community dwelling wheelchair users. The creation and validation of this tool is an important first step in developing treatment strategies that could address low confidence with wheelchair mobility. Ultimately, this work could result in better mobility and independence for people who use wheelchairs, and a decreased burden on the health care system and on caregivers.
Effect of cam-type deformity associated with femoroacetabular impingement on hip mechanics
Hip osteoarthritis (OA) is a painful condition affecting 4.4 per cent of the population aged 55 and older. Currently, there are very limited treatment options and no known cure for OA. Improving prevention and treatment of early hip OA requires a thorough understanding of the joint mechanics and how these mechanics affect the initiation and progression of the disease. Hip OA can either be primary (occurs with no previously known cause) or it can be secondary to a known deformity. It has recently been hypothesized that most “”primary”” cases are actually caused by small deformities in the joint that were previously unnoticed. One deformity that has been found to have a strong correlation with hip OA is called a cam deformity, which can cause pain and decreased range of motion in the hip. Cam deformities occur on the upper femur (thigh bone) and cause increased contact between the femur and the acetabulum (hip socket). Joint contact pressure is thought to play a role in accelerating the onset of OA. To determine the association between cam deformity and the onset of hip OA, Laura Given is studying how the joint mechanics change depending on the degree of cam deformity. She will track how the joint translations and rotations are affected throughout the range of motion of the hip and determine how the range of motion is affected by simulated cam deformity. By describing how the size of cam deformity affects joint mechanics, Givenâs research will help surgeons understand how to effectively correct the deformity in an effort to slow or even stop the osteoarthritic disease progression. It could also lead to preliminary guidelines in arthritis screening programs. This could reduce the number of cases of hip OA seen in the future.
Protein tyrosine phosphatase A (PtpA) dependent mycobacterial manipulation of host response to infection
Tuberculosis (TB) is currently the worldâs leading cause of mortality due to a single infectious agent. It has been estimated that approximately one-third of the worldâs population is infected with Mycobacterium tuberculosis, the bacteria that causes TB. Approximately two million people die of TB annually, and about eight million new cases arise each year. In addition to the emergence of multi-drug resistant strains of the disease, TB develops much more readily in people with HIV infection, and is a leading cause of AIDS-related death. There is an urgent need for novel therapeutics and drug targets in order to control the global spread of TB. In order to evade attack by the host immune system, M. tuberculosis secretes a protein called Protein tyrosine phosphatase A (PtpA). PtpA interacts with multiple proteins in the host that are normally essential for the destruction of bacterial pathogens. However, the exact role of these interactions in relation to the survival of M. tuberculosis within cells is not yet completely understood. Dennis Wong is defining the role of TB-Host interactions and identifying the molecular events that are disrupted by PtpA to promote TB infection. Understanding the mechanisms by which PtpA promotes the survival of M. tuberculosis will provide important insights regarding the pathogenesis of TB and the response of the host immune system to infections. As PtpA is a potential drug target, the new knowledge may contribute to the development of novel therapeutics against one of the deadliest diseases in the world.
Translational TB Research: Identification of Novel Drug Targets and Development of Protective Vaccines
A recent report from the World Health Organization revealed that about 1.5 million people died from TB in 2006. In addition, another 200,000 people with HIV died from HIV-associated TB. Current strategies aim to reduce the annual death toll from TB to less than 1 million worldwide by 2015, as set out in the United Nations Millennium Development Goals. Infection by the Mycobacterium tuberculosis microorganism causes TB. The current global strategy for TB control is based on reducing the spread of infection through massive vaccination campaigns with the BCG (bacille Calmette-Guérin) vaccine, and treatment of individuals with active disease using multi-drug combinations. However, there are challenges to this approach, including inefficiency of the BCG vaccine, the emergence of drug resistant strains of Mycobacterium tuberculosis (Mtb) and the difficulty in delivering a treatment that requires multiple drugs over periods of six months or more.
Until recently, little was known about how Mtb alters the host immune system to cause infection. Through Dr. Zakaria Hmama’s work as an MSFHR Scholar over the past six years, important new knowledge has been developed regarding the sub-cellular and molecular mechanisms of host/pathogen interactions. His research over the next five years will focus on gene manipulation technologies to upgrade the current BCG vaccine with recent immunological concepts to maximize its protective properties. Hmama is also investigating an important virulence factor identified by his lab as a potential drug target for TB treatment.
Translating gene expression into clinical care for sarcomas and breast cancer
Cancer is one of the leading causes of death in Canada. As a pathologist, Dr. Torsten Nielsen’s job is to accurately diagnose cancer and determine its type from more than 200 possibilities. For more than 50 years, these diagnoses have been made using a light microscope to examine tissue biopsies. However, this can be subjective, requiring the pathologist to make a judgment call in certain cases. Recent new technologies help determine the genetic profile of each type of cancer. This profile can be used to distinguish between cancers that otherwise appear almost identical under the microscope. The ability to detect subtle differences among cancers can be enormously important because the exact diagnosis determines what combination of surgery, radiation, hormone treatment or chemotherapy is the best treatment plan.
Using advanced genetic tools, Dr. Nielsen aims to develop clinical tests that more accurately identify difficult subtypes of cancer, and to then determine which treatments will work best for each subtype. Previously supported by an MSFHR Scholar award, he works with two cancer types in particular: breast cancer and sarcomas (tumours of muscle and bone). With breast cancer, he is working to develop inexpensive and easy-to-conduct clinical tests that accurately diagnose four types not easily distinguished under the microscope. With sarcomas, he is using new molecular tools to develop diagnostic tests and treatments that target specific molecular changes, to see if new drugs can cure these cancers with minimal side effects. His research could lead to simple, effective, and widely available diagnostic tools and personalized treatment strategies that will improve survival for cancer patients.
The role of SHIP's C2 and PH domains in regulating hematopoietic cell growth and function
Various cancers and inflammatory diseases occur as a result of inappropriate activation of the bodyâs blood-forming hematopoietic cells. Normally, cellular activation, growth and survival in hematopoietic cells are regulated by the phosphoinositide 3-kinase (PI3K) pathway, which drives a wide range of cellular processes. Keeping tight control on this pathway is SHIP (SH2 domain-containing inositol 5′ phosphatase), a counteracting enzyme that inhibits PI3K action. SHIP is found only in blood and immune system cells and is the major restraining mechanism in these cell types. Loss or impaired activity of SHIP â in effect, removing the brakes on the PI3K pathway â has been implicated in certain leukemias and in inflammatory disease. Recently, researchers discovered small molecules that are capable of enhancing SHIP activity, resulting in both the inhibition of immune cell activation and the death of hematopoietic cancer cells. This represents a previously unknown mode of regulating SHIP enzyme activity. Andrew Ming-Lum is determining the significance of this novel type of regulation of SHIP function. Using cell lines and mouse models, he is focusing on a previously unrecognized domain on the enzyme, upon which the small molecules are believed to act. These studies will provide greater insight into how this mechanism affects the function, growth and survival of hematopoietic cells. It will also provide insight into the dysregulation that occurs in certain cancers and inflammatory diseases.
Preventing falls and disability in older adults after hip fracture
Every year, more than 20,000 people in Canada sustain a hip fracture. Of these, up to 20% die within 12 months and 50% do not return to their pre-fracture level of mobility. People who have a hip fracture have a higher risk of falling and an increased risk of a subsequent hip fracture compared with those of the same age who have never had a hip fracture. After a hip fracture, relative immobility initiates a vicious cycle where deteriorating balance and muscle weakness increases risk of falls and diminished bone health contributes to fracture risk. Although exercise is key to reversing this pattern, there have been relatively few clinical trials aimed at improving muscle strength, balance and enhancing bone health following hip fracture.
Dr. Maureen Ashe is conducting a randomized controlled trial to evaluate the impact of a targeted exercise program on the rate of falls, functional mobility and bone micro-architecture among older adults who have sustained a hip fracture. If successful, this intervention will result in fewer falls and improved bone health in a vulnerable senior population. Data from the research will inform recommendations for rehabilitation and contribute to the knowledge base for health-professionals, both in hospital and in the community, who manage care after hip fracture.
The characterization of KiSS1 and GPR54 in breast cancer and other hormonally responsive cancers
Cancers whose growth is influenced by sex hormones, such as estrogen and testosterone, form the largest group of cancers that affect Canadian men and women. Breast cancer remains the second most common cause of cancer death among women in North America, and prostate cancer rates third for men. While there have been advances in treatment, many of these patients will succumb to their disease when tumors metastasize (spread to other organs or tissues in the body). The KiSS1 and GPR54 genes have demonstrated the ability to prevent metastases from developing. While the importance of KiSS1 and GPR54 are being studied in other cancers, little has been done to investigate the involvement of these two genes in clinical breast and ovarian cancers, and no studies have been conducted in prostate cancer. Building on her MSFHR-funded Masterâs research, Leah Prentice is investigating whether KiSS1 and GPR54 have dual roles as both tumor promoters, via their involvement in hormonal processes, and also as suppressors of metastasis. By understanding the anti-metastatic mechanism of these two genes, Prentice hopes to contribute to the development of more targeted therapies and diagnostic tests that would allow for earlier detection of these potentially life-threatening cancers.