Emphysema is a destructive lung disease that obstructs the airways and compromises oxygen transfer from the lungs to the bloodstream, causing a decrease in respiratory function. More than 1,100 people die of the disease in Canada each year. Currently, there are no treatments to cure emphysema. Cigarette smoking is the major risk factor for developing the disease. Yet only 15 to 20 per cent of smokers develop symptoms. An increase in protein-degrading enzymes called proteinases is believed to play a role in the origin of emphysema. Previous studies also suggest a genetic predisposition to airflow obstruction. Variations in the genes regulating these proteinase enzymes may be responsible for individual differences in response to cigarette smoke. Alison Wallace is researching whether genetic variants in proteinases increase smokers’ susceptibility to emphysema. If so, this information would help identify people at risk for the disease, contributing to early promotion of anti-smoking strategies and possibly leading to new methods for early detection and treatment. In addition, drugs that inhibit proteinases could be targeted to patients predisposed to emphysema, but unable to quit smoking.
Research Pillar: Biomedical
Early progression and detection of ovarian cancer
In developed countries, ovarian cancer is the leading cause of death from gynecologic malignancies in women. The five-year survival rate is only 35 to 40 per cent, a rate that hasn’t changed significantly in 25 years. The poor prognosis is due to the lack of a reliable test for early detection and the inability to identify early symptoms of the disease, which means the majority of ovarian tumours are diagnosed at an advanced stage. During progression to malignancy, normal ovarian surface epithelial cells, which give rise to the majority of epithelial ovarian cancers, acquire more complex and highly differentiated characteristics that most often resemble epithelial cells in the fallopian tube and uterus. This change may provide an advantage for growing cancer cells. Michelle Woo is screening ovarian tumour tissues for markers known to be present in the fallopian tube and uterus. She has recently discovered a protein in ovarian tumours that may be an early indicator of ovarian cancer. Another approach she is using to examine early changes in ovarian tumour progression involves the use of a unique three-dimensional culture system to mimic the development of ovarian tumours in women. Michelle hopes this research will identify new predictive markers that can be used for early screening and prevention of ovarian cancer.
Molecular analysis of transplant recipients
One of the major problems for patients who have undergone heart or other transplants is the potential for the body’s own immune system to attack the newly introduced organ. As a result, patients must take large doses of immunosuppressive drugs daily to prevent rejection of the new organ, which the body perceives as foreign. Unfortunately, these medications interfere with normal immune response, which leads to a wide range of dangerous side effects, including higher susceptibility to infections and cancer. Dosage must be carefully monitored: not enough, and the body will begin to reject the organ; too much, and patients must deal with the serious side effects. The goal of Edward Chang’s work is to develop new genetic tests to predict exactly how much medication each individual patient requires to ensure the organ is accepted with minimal side effects.
Identification of genes key to the progression of squamous cell carcinoma of the lung by 3p array comparative genomic hybridization
Lung cancer accounts for the majority of cancer deaths in Canada. Unfortunately, diagnosis typically occurs after lung cancer is well-established, too late for effective treatment. To develop more effective ways of detecting and treating cancer, researchers are studying the genetic makeup of patients, with the goal of identifying and characterizing particular genes that may either suppress or promote the onset and progression of lung cancer. Using an approach that combines laboratory benchwork with bioinformatics techniques (the use of computer tools and databases to analyze large amounts of biological data), Bradley Coe is focusing his work on a specific chromosome, 3p, with which genetic alterations have recently been linked to the development of lung cancer. Identifying genes critical to the disease process will lead to a better overall understanding of lung cancer and may point the way to more targeted diagnostic tests and treatment.
Cellular excitation contraction coupling of intact airway smooth muscle
Diseases of the airways, such as asthma, are often characterized by excessive constriction of tissues caused by the over-contracting of smooth muscle cells. This contraction can severely impair breathing and compromise oxygen exchange between the lungs and blood system. Calcium is a major activator of smooth muscle cell contraction, and the concentration of calcium within cells determines the extent of contraction. Using intact airway muscle tissues, Jiazhen Dai is undertaking an extensive survey of the pattern and the mechanisms of calcium-dependent contraction in both healthy and diseased airways. In particular, she will investigate a newly-uncovered pattern of asynchronous, wave-like calcium oscillation to assess its role in airway constriction. This research will provide a better understanding of the mechanisms of airway constriction and ultimately, new drugs to effectively treat respiratory conditions such as asthma.
Identification of gene regulatory changes involved in cancer progression by gene expression studies and bioinformatic analyses
Obi Griffith was part of a team at the BC Cancer Agency’s Michael Smith Genome Sciences Centre, that cracked the genetic code for Severe Acute Respiratory Syndrome (SARS) in April 2003. In his MSFHR-funded research, Obi is examining how changes in the regulatory sequences of DNA may lead to cancer. By comparing the activation patterns of clusters of genes in normal and cancerous tissue, Obi is working to identify genes that undergo a change in regulation leading to cancer. Once these cancer-causing mutations are identified, he will investigate the biochemical mechanisms responsible for these regulatory changes. Learning more about specific gene regulation changes that lead to cancer may lead to new ways to diagnose, predict and treat cancer using gene-based therapies.
Regulations of the endocannabinoid receptor system of glucocorticoid hormones: Implications for Schizophrenia
The onset and development of many mental illnesses, such as schizophrenia, are believed to be affected by stress and the hormones produced as a result of stress. Research has shown that these stress hormones act upon receptors in the brain that interact with the endocannabinoid system. The endocannabinoid system is a neurochemical system which contains receptors that respond to both cannabis (marijuana) and naturally produced substances known as endocannabinoids. People with schizophrenia have been shown to have elevated levels of naturally-occurring endocannabinoids, and there is evidence that alteration of the endocannabinoid system through the use of marijuana reduces the effectiveness of anti-psychotic medication. Matthew Hill is investigating links between the endocannabinoid system, exposure and hormonal responses to stress and the development of schizophrenia. Matthew’s research may improve understanding of the neurobiological mechanisms involved in schizophrenia and suggest future treatments to manage this mental illness.
Role of Nrf2 mediated transcriptional events in neuroprotection during stroke
Free radicals are potentially damaging molecules produced in cells, particularly in response to injury. Certain free radicals cause tissue damage and trigger cell death. To combat the effects of free radicals, healthy people produce adequate quantities of antioxidants, scavenging enzymes that defend cells from free-radical destruction. When a person suffers a stroke, free radicals known as reactive oxygen species may cause cell death in large areas of the brain, resulting in brain damage and disability. It is believed that by increasing the number of antioxidants in the brain, cell death and damage following stroke might be minimized. Sophie Imbeault is working to clarify the role of the transcription factor Nrf2, which regulates the production of antioxidants in the brain. By studying the basic mechanisms underlying Nrf2 activation both during normal functioning and during stroke, she hopes her work will ultimately point to new treatment possibilities for minimizing stroke damage.
Mechanistic investigations of retaining glycosyl transferases from Neisseria meningitidis and Saccharomyces cerevisiae
The complex arrangement of carbohydrates that cover the surface of cells is known to play a key role in gene activation and cell-to-cell recognition processes. Changes in the composition of these carbohydrates can lead to many pathological conditions, including the proliferation of cancerous cells and compromised immune function. Research suggests that elevated activity in the enzymes that place these carbohydrates on the cell surface is primarily responsible for changes in cell surface composition, however, the chemical mechanisms these enzymes use to function are not well understood. Working in collaboration with the McGill Cancer Centre in Montreal, Luke Lairson is researching how these enzymes function. This knowledge may be used to design effective new drug therapies to inhibit enzyme activity and help prevent and treat various human diseases ranging from cancer to AIDS.
Identification of Phosphoregulation pathways involved in Hematopoetic Stem cell self-renewal
In recent years it has been suggested that hematopoietic stem cells (HSCs) possess the ability to develop into different types of tissue in the body. Conceivably this phenomenon could one day facilitate treatment of a variety of degenerative diseases via harvesting a patient’s own HSCs, genetically modifying them, and then transplanting them back into the body. Unfortunately at present there is no effective way to maintain HSCs outside of the body, as the cells self-renew only in response to the unique combination of growth factors present within the specialized environment of the bone marrow. Michael Long is comparing how different environments affect the pathways by which HSCs receive chemical signals to renew. By studying HSC activity within bone marrow as well as an environment that does not promote HSC renewal such as the spleen he hopes to determine which signalling pathways are vital for HSC renewal. Ultimately, this information may allow researchers to identify how to recreate an environment outside the body that promotes HSC growth.