Parvoviruses are small, single stranded DNA viruses that must enter the nucleus of their host cells in order to replicate. Because of their ability to target and kill rapidly dividing cancer cells, parvoviruses have recently gained attention as potential vectors (carriers) for use in cancer gene therapy. Although research has led to a better understanding of cell entry and trafficking of parvoviruses, little is known about how parvoviruses are imported into the nucleus. Sarah Cohen is continuing her earlier MSFHR-funded research which examined how a specific parvovirus, Minute virus of mice (MVM), enters the cell nucleus. Cohen’s research discovered that MVM selectively breaks down the membranes surrounding the nucleus, the nuclear envelope (NE), in the early stages of infection. Now, she is investigating how parvoviruses disrupt the nuclear envelope of host cells and whether this disruption allows the MVM access into the cell nucleus. Cohen’s goal is to determine whether parvoviruses initiate the process leading to cell death (apoptosis) early in an infection. If so, it may be possible to boost the anti-cancer activity of parvoviruses, by engineering them to produce additional proteins that can kill cancer cells. Ultimately, this research could show MVM is a viable anti-cancer agent for clinical studies.
Year: 2007
The regulatory role of matrix metalloproteinase-8 in inflammation and autoimmunity
Rheumatoid arthritis affects one in six people. Although the specific trigger is unclear, the condition occurs when the immune system mistakenly attacks tissue within the joints. Symptoms include swelling, pain, stiffness and redness caused by an accumulation of white blood cells in and around the joint. When the inflammation persists for a long time, it may cause irreversible cartilage damage and bone erosion, leading to deformity and disability. In her previous MSFHR-funded research, Jennifer Cox examined molecular influences on the immune system. Now she is focusing on understanding the inflammatory process in the development of arthritis. Jennifer is studying MMP-8, a member of a family of enzymes called matrix metalloproteinases that function to break down proteins in the body. This process, called proteolysis, is essential for normal immune responses. However, an unusually high level of MMPs may contribute to diseases such as arthritis and cancer. For example, elevated levels of MMP-8 are present in patients with rheumatoid arthritis. Jennifer is researching whether MMP-8 contributes to the progression and severity of the disease, or conversely if the high levels of enzyme are protecting against inflammation. Her findings will contribute to a better understanding of the inflammatory process and potentially to new methods for treating rheumatoid arthritis.
Epigenomic variation in normal and cancer cells
Tumour suppressor genes (TSGs) are DNA blueprints for proteins that stop cells from dividing and increasing in numbers. Each TSG comes in pairs called alleles: one from the mother and one from the father. Cancer is caused by the uncontrolled division of cells; in order for cancers to grow, both tumour suppressor alleles need to be turned off. It was previously thought that the only way to turn off genes like TSGs was through permanent changes to the normal DNA sequence, called mutations. However, another way to turn off genes is to add small chemical “tags” – called methyl groups – to a gene. This causes the DNA blueprints to fold up and become unreadable. Another complexity is that some regions of DNA that are normally folded up because of methylation become de-methylated as cancer progresses. This turns on cancer-promoting genes and increases DNA instability. Therefore, it is important to determine the DNA methylation patterns of all DNA in cancer cells in order to know what and how genes are turned on and off. Jonathan Davies previously received a Junior Graduate Studentship from MSFHR. Now funded with at Senior Graduate Studentship, he is researching techniques to identify genes and regions in normal and cancer genomes that may be turned on or off by DNA methylation. These techniques could be used to tailor treatments to individual patients, leading to improved recovery rates, and avoiding costly and ineffectual treatments.
In vivo imaging of neuronal growth and connectivity during activity-dependent learning within the developing brain – exploring the link between morphology and function
In development, neurons form complex connections within the brain that ultimately determine how you think, how you feel, how you act and how your body communicates with itself. In the past, researchers believed that our genes were the main determinants of brain development. Now an increasing number of studies show that conditions in our surroundings can influence our internal brain plan during early life and in later years. One of the most interesting questions in brain development is whether the shape and structure of individual neurons is connected to the function that those neurons play within our brains. Using real-time imaging of the shape and structure of single neurons during development, Derek Dunfield is investigating how neurons grow and connect with each other and how external activity influences these connections. His studies include using external activity to modify the functions of neurons and see if this affects their structure. By developing a better understanding of the connection between a neuron’s function and its growth or ability to form brain circuit connections, Dunfield’s research could provide useful knowledge about how information is stored within our brains. The study of how external activity modifies both the structure and function of neurons may shed light on how aberrant brain circuits form and can lead to disabling brain disorders later in life.
In Vivo Evaluation of the Potential Role of Anti-Inflammatory Factors Involved in the Survival and Mechanism of Action of hRPE-Cell Implants for Parkinson's Disease
Parkinson’s disease is a neurodegenerative disorder that causes tremors, muscular rigidity, slowness of movement and postural instability. Affecting up to three per cent of the elderly population, Parkinson’s is characterized by depletion of the neurotransmitter dopamine and chronic inflammation in the substantia nigra region of the brain. While various pharmacological treatments alleviate symptoms of the disease, these medications eventually lose effectiveness and cause debilitating side effects. Cell-based transplantation therapies are being studied as alternative treatment options for Parkinson’s disease, but the routine use of these therapies has been delayed by mixed clinical results, safety and logistical concerns, and ethical issues. Recently, human retinal pigment epithelial (hRPE) cells have been proposed as a tissue transplant alternative for Parkinson’s disease and are currently being used in Phase II clinical trials. Found in the inner retina, hRPE cells are easily grown in culture so that a single donor can provide sufficient tissue for multiple recipients. Several studies have shown sustained reversal of Parkinsonian symptoms after hRPE implants with minimal side effects. Especially interesting is early evidence suggesting that transplanted cells may have the potential for long-term survival without requiring immunosuppressive drugs. However, little is known about the mechanisms of action of hRPE cells. Joseph Flores is researching the survival of implanted hRPE cells and the ability of implanted hRPE cells to replace depleted dopamine and induce a long-term anti-inflammatory response. A better understanding of hRPE-cell implants may lead to its routine use as a therapeutic alternative for Parkinson’s disease and improved outcomes for patients.
Independence of identity and expression? A look at facial processing in both healthy and patient populations
Recognizing facial expressions and identities plays a crucial role in daily life. People who have experienced damage to identity recognition regions of the brain due to stroke, trauma or other causes are unable to recognize the identity of faces, often including their own. People with damage to regions involved in expression recognition have difficulty interpreting expressions, which leads to social mistakes. Problems in expression recognition may have a role in autism and other social developmental disorders. Studies have suggested that specific brain regions are primarily involved in either facial identity recognition or facial expression recognition. However, recent studies, including research Christopher Fox has contributed to, suggest the two are not restricted to independent regions. Fox is designing a series of psychophysical tests to determine the extent of the overlap and using functional magnetic resonance imaging to measure brain activity in both healthy individuals and those who have experienced brain damage. Fox aims to determine whether an area of the brain previously thought of solely as an expression recognition region is also able to process facial identity. The research could lead to new therapies for people with facial recognition disorders. Fox was funded as a 2005 trainee award recipient for research on the role of the temporal lobes in vision and the process of visual perception.
Neuropsychological predictors of medication adherence and employment status following kidney transplantation
For her Master’s research, supported by a 2005 MSFHR Trainee Award, Shannon Gelb researched whether cognitive difficulties (brain functions such as memory and reasoning) exist following a kidney transplant. The research revealed that adult recipients of kidney transplants tend to perform worse than healthy individuals without transplants in tests of verbal memory (the ability to recall verbal information after a delay period) and executive functioning (activities such as multi-tasking and problem-solving). However, the impact of these results on daily life is unclear. Building on this research, Gelb is examining the relationship between cognition and two functional outcomes for kidney transplant recipients: adhering to prescribed medications and maintaining employment. Not taking medication properly, which is associated with increased risk of the body rejecting the transplanted kidney, is a significant problem among kidney transplant recipients. Employment rates among kidney transplant recipients are also poor – 59 to 83 per cent of kidney transplant recipients never return to work following kidney transplantation. The research may help clarify the potential need for increased education and patient support following kidney transplantation.
The effectiveness of a supplementary inpatient exercise program on upper limb function in individuals with stroke
After a stroke, 80 per cent of people have long term difficulty using the arm and hand on one side of their body. This can lead to a loss of independence and a decrease in quality of life. Most rehabilitation of the arm and hand after a stroke takes place in hospital; however, while recent research indicates that approximately one hour a day of arm therapy is needed to improve the arm’s ability to be useful in daily activities, the time currently spent on arm-specific treatment is only 20 to 30 minutes. Jocelyn Harris is studying the implementation of an in-patient exercise homework program that increases the amount of arm therapy a patient performs in hospital. Taught by a therapist, the homework exercises are done for one hour a day, five days a week, for four weeks. Before starting the program and at the conclusion of the four weeks, patients participate in tests to measure hand strength, arm and hand movement, and the ability of the arm and hand to participate in day-to-day activities. This study will determine if increasing the amount of arm therapy time increases the ability to use the arm among stroke patients. An increase in ability can ultimately contribute to improved independence, continued community living, better health and enhanced life satisfaction among people who have had a stroke.
What Causes Parkinson's Disease? An Epidemiologic Analysis of Occupational Exposures
An estimated 100,000 Canadians have Parkinson’s disease, a neurodegenerative disorder that affects the body and brain, causing tremors, stiffness and impaired mobility. Dopamine is a chemical produced in the brain to carry signals between nerves. Parkinson’s develops when cells that produce dopamine die. Researchers have yet to determine what triggers the onset of Parkinson’s. Although a small proportion of cases seem to run in families, research indicates the explanation may lie in individual environmental and lifestyle exposures. For example, workplace exposure to chemicals such as pesticides, heavy metals and solvents may increase the risk of developing Parkinson’s. In one of the largest studies to examine Parkinson’s disease, Anne Harris is investigating whether exposure to the “whole-body vibration” workers can experience operating heavy machinery also elevates risk. Previous studies have shown that traumatic head injury from boxing and other activities can damage the part of the brain that produces signals crucial to mobility and brain function. Harris wants to determine whether the accumulation of smaller injuries over time from whole-body vibration also damages this part of the brain. Her findings could lead to new methods for preventing and treating Parkinson’s disease.
Safety of home birth: Consequences of hemorrhage in home birth
The safety of home birth for women at no identifiable risk is a controversial issue. Approximately 40 per cent of women accessing midwives in BC choose to give birth at home. If there is an emergency related to birth, access to definitive care can be delayed by geography, weather and timing of labour. Severe hemorrhage (bleeding) during childbirth is a clinical emergency that requires immediate invasive interventions by specialized health professionals. It is one of the top three leading causes of death among mothers. Survivors are at risk of developing kidney damage, surgical removal of the uterus and adverse events associated with blood transfusions. But little is known about the consequences of hemorrhage in home birth. Eman Hassan is researching the risk of developing serious consequences following hemorrhage in the home birth setting. She is comparing rates of unfavourable events that occurred due to hemorrhage among planned home births and planned hospital births in the period 2002-2004. The study will provide important information to practicing midwives and childbearing women about what may contribute to hemorrhage, who is at greater risk of developing these events, and the factors that may affect timely access to specialized care. This information will help prevent serious health problems among women considering home birth in BC, and will also be applicable to other provinces in Canada.