One challenge with treating solid tumours is ensuring the effective delivery of chemotherapy drugs to all the cells within a tumour. Inefficient penetration of an anti-cancer drug results in insufficient doses reaching cells distant from the tumour’s blood vessels. As a result, these cells may survive and proliferate, allowing the tumour to re-grow. In addition, a low drug exposure may actually contribute to tumour cells developing resistance to a drug. Lynsey Huxham is examining the tumour microenvironment after drug administration and determining which drugs penetrate well. She is focusing on the effects of a drug by examining dividing cells and those undergoing apoptosis (cell death) in relation to their distance from blood vessels. By understanding the process of extra-vascular drug distribution, she hopes to aid efforts to improve the administration and delivery of cancer drugs, as well as offer insight into the design of new chemotherapy drugs.
Year: 2005
Mechanism of valproic acid-induced hepatotixicity
Valproic acid is an anticonvulsant drug frequently prescribed to epileptic patients, and also used to manage bipolar disorder, migraine headaches and pain. Despite its ability to control seizures, the drug is associated with a rare, but potentially fatal liver toxicity. It is unclear how valproic acid causes liver failure, and health care professionals are unable to predict which patients will be affected, although it occurs more frequently in patients younger than two years of age who are also taking other anticonvulsant medications. Tony Kiang is researching the factors that cause and the mechanisms responsible for valproic acid induced liver failure in pediatric epileptic patients. The research could help physicians identify patients at risk of liver toxicity before prescribing valproic acid, so other medications can be used instead. The findings could also be applied to other drugs with similar side effects to improve their safety, and to identify compounds likely to cause side effects during drug development.
Glutamate regulation at the Drosophila larval neuromuscular junction: a model for excitatory synaptic function
The human brain is composed primarily of two cell types – neurons, which extend axons that make contact with other neurons at synapses, and glia, which wrap around neurons, protecting them and regulating their function. An electrical signal is conducted through the axon to the synapse where neurotransmitters are released to electrically excite the next neuron. The termination of this chemical signal is controlled by nearby glia, which remove the neurotransmitter using transporter proteins on their cell surfaces. A malfunction in this activity may lead to excessive levels of neurotransmitter accumulating in the synapse, over-exciting nearby neurons and glia and eventually leading to cell degeneration and death. This type of glial malfunction has been linked to many common neurodegenerative diseases (e.g. stroke, Alzheimer’s, multiple sclerosis and muscular dystrophy). Glutamate, the neurotransmitter at most brain synapses, is also present at many synapses of the fruit fly (Drosophila melanogaster). As in humans, fly glia have glutamate transporters that are thought to regulate synaptic communication. Robert Parker is studying glial neurotransmitter transporter function in the fruit fly, altering the amount of glutamate transporter present in glial cells near the Drosophila neuromuscular junction (a synapse between a neuron and a muscle cell) which may cause the over-excitation, degeneration and death of nearby cells. By studying the basic function of glutamate transporters in flies, he hopes to gain a greater understanding of the clinical importance of glutamate transporters in many human neurodegenerative diseases.
High resolution analysis of rearrangements in follicular lymphoma genomes using high-throughput BAC clone fingerprinting
Follicular lymphoma is a cancer of the lymphocytes (cells of the immune system) and is the most prevalent type of lymphoma in Canada. Most follicular lymphomas are associated with defective cells resulting from the gene regulation process (the process through which the cell determines when and where genes will be activated) resulting in increased production amounts of the protein Bcl-2. This protein prevents lymphocytes from dying at the end of their natural lifespan, causing these altered cells to persist in the body, gain abnormal alterations in their genomes, and eventually develop into cancerous cells. Anca Petrescu is examining how chromosomes in follicular lymphoma are structurally different and rearranged relative to the normal genome, and how these differences may cause cancer. She is studying ten follicular lymphoma genomes and will profile each to discover the rearrangements they harbour. Common rearrangements will be analyzed in detail to determine their exact properties, and their effect on genes. Anca hopes her research will provide insight into the role of recurrent rearrangements in follicular lymphoma, and allow for further research to identify key genes that may be may be of potential diagnostic or therapeutic use.
A potential role for KiSS1 overexpression in tumorigenesis and metastasis of breast cancer and other hormonally responsive tumors
Breast cancer is the second most common cause of death due to cancer among women. One in nine Canadian women will develop breast cancer during her lifetime, and one in 27 will die from the disease. Despite advances in treatment, many women experience metastasis, where the tumor migrates from the original site to other organs or tissues in the body. Leah Prentice is investigating whether the KiSS1 gene has a dual role in breast cancer, which involves increased numbers of the gene driving tumour growth at an early stage, but suppressing metastasis at a later stage. Research indicates KiSS1 prevents metastasis from developing, but it’s unclear how the gene accomplishes this. She is studying the role of the KiSS1 gene in synthesizing and releasing sex hormones like estrogen. Estrogens initially promote the grow th of breast cancers, but this effect is usually lost as the tumor progresses and metastasizes. The research could lead to diagnostic tests to detect breast cancer earlier, and more targeted therapies to treat breast cancer and prevent metastasis.
The effects of an acute bout of exercise on alpha-receptor responsiveness and orthostatic tolerance in hypertensive individuals
Hypertension (high blood pressure) is a major public health issue. About 22 per cent of Canadians have hypertension, a risk factor for numerous cardiovascular diseases, including stroke, coronary heart disease, kidney failure and narrowing of the blood vessels to the arms, legs and feet. Jessica Scott is examining the effects of exercise in people with mild or moderate hypertension. Previous studies have shown an eight to 10-week physical exercise program can dramatically reduce blood pressure in hypertensive individuals. But the striking decrease in blood pressure immediately following exercise may be dangerous for these patients. While standing, gravity displaces blood away from the middle region of the body and pools in the extremities, reducing the volume of blood available to the heart. Fainting after exercise as a result of this pooling in the extremities may be the first indication of a serious cardiovascular condition. Jessica is investigating whether a sudden drop in blood pressure predisposes people with hypertension to lose consciousness following exercise. Ultimately, she aims to develop a safer, more effective exercise program for people with high blood pressure.
Exploring a community approach to enhance the healthy development of youth
Youth across BC are exposed to a variety of risk factors that can inhibit their ability to develop into healthy adults. Some of these risks include alcohol and drug use, gambling, physical and sexual abuse, harassment and discrimination, obesity, and feeling unsafe at school. Most funding agencies support one-time projects to improve health and social outcomes among youth. Although these interventions are intended to target needs identified by the community, many are unable to generate long-term change toward healthy youth development, because of short-term grants, competing goals, a lack of trust in the community and uneven volunteer support. Carol Sparks is studying how an alternative approach—community action projects—creates sustainable change. Community action shifts the focus from one-off projects to a community-centred approach, based on the belief that families provide the primary support for children and youth, and vulnerable youth need community support to meet their health and social needs. Carol is working in collaboration with the communities of Courtenay and Campbell River on Vancouver Island to determine the processes used by local community action projects to address the social and economic determinants of youth health. This research will identify both barriers to sustainability and strategies that support sustainability.
Tracking the differentiation fate of islets from pancreatic endocrine progenitors via expression of lentivirally transduced fluorescent reporter genes
The recent success of a pancreatic islet cell transplantation procedure known as the ‘Edmonton Protocol’ gave new hope for a better treatment of type 1 diabetes (insulin dependent diabetes), compared to the current treatment via insulin therapy. However, a shortage of donor pancreatic tissue means an alternate source of transplantable cells is needed. Insulin-producing islet cells are created from pancreatic precursor cells through a process called differentiation. However, not all pancreatic precursor cells give rise to insulin-producing islet cells. Further, the optimal conditions for differentiating these cells have not been determined. This poses a challenge for researchers attempting to identify and isolate the specific precursor cells needed for producing transplantable islet cells on a large scale in the laboratory. Marta Szabat is working to develop a functional assay for tracking the differentiation fate of islets from pancreatic precursor cells using fluorescent reporter genes. This cell marking technique would flag only those cells with specific genetic characteristics, allowing for purification and further characterization of labeled cells. Using this functional assay, her long term objective is to determine the optimal conditions to support (culture) the differentiation of pancreatic progenitors into insulin-producing cells.
Computational identification and quantitative modeling of dynamic cellular pathways
The ability of cells to carry out life functions arises from the collective behavior of interacting molecules. Cells are able to integrate multiple internal and external messages simultaneously and respond reliably with a predefined set of outcomes. This adaptability and robustness is based on a complex system of signaling and regulatory molecules, which interact in dynamic circuits to regulate and support all aspects of cell growth and function. James Taylor brings a background in engineering physics to the study of molecular biological systems. He is using mathematical and computational modeling to simulate information flow through dynamic molecular circuits. In parallel, he is designing microfluidic platforms for the experimental testing of these circuits on the single cell level. James hopes to increase the efficiency of biological discovery and the use of predictive modeling in drug discovery. Employing filamentous form cell differentiation in yeast as a model system, he is characterizing the dynamics of a new circuit within the MAP Kinase cascade, a common signaling system that plays a central role in integrating the signals from a diverse group of external stimuli to regulate processes such as cell proliferation, cell differentiation, cell movement and cell death. Using a double headed approach of modeling and experimentation, he is continuing to research how this complex circuit enables the cell to robustly integrate multiple internal and external molecular messages simultaneously.
Back injury in heavy industry: Examining peak and cumulative back muscle activity for risk exposure assessment
Despite increasing technological advances, heavy industries remain physically demanding, with high back injury rates among workers. In BC, more than 17,000 compensation claims for back strain accounted for 25 per cent of all claims for 2001. More than a quarter of these claims come from employees in the forestry, wood and paper products, construction, transportation, and warehousing industries. Activities such as lifting, carrying or pushing objects subject workers to forceful exertions, repetitive movements and awkward postures, all of which can contribute to back injuries. Injuries are thought to be caused by both “peak” or maximal loads (such as lifting a heavy box once) and the total load over time (repeatedly lifting boxes throughout the day). However, most studies have focused solely on peak loads. Catherine Trask is conducting the first study to measure muscle loading over time among workers in these five heavy industries. Catherine is comparing how peak and cumulative muscle loads impact back strain, and whether total load is an important risk factor for back injury. The results may identify the maximum safe physical loads for workers in heavy industry, which would help reduce injuries, make industrial workplaces safer, and reduce claim costs.