The Hereditary Cancer Program at the BC Cancer Agency provides genetic testing and counseling services. The demand for these services in BC depends on many factors, each of which is subject to change. Factors include the growing knowledge in basic, applied and social sciences relating to hereditary cancer; the size of BC’s population and its characteristics in terms of age, ethnicity and family size; the evolving criteria by which people are deemed eligible for services; and people’s desire for these services. Through his research, Dr. Chris Bajdik is determining the demand for hereditary cancer services in BC and predicting how this demand may change in the future. He has created a computerized simulation model of the BC population, based on information about demography, cancer epidemiology and etiology, genetics, genetic technology, and human behaviour. The results from this model will help the BC Cancer Agency plan its services and assess the health benefits and costs of its Hereditary Cancer Program.
Program: Scholar
Structural analysis of the bacterial Sec-dependent protein secretion system
Cells have compartments separated by membranes. Many proteins are made in one compartment but actually function in another. The ability of proteins to travel across membranes within cells is essential to cell life. Malfunctions in this process can lead to a variety of inherited and autoimmune diseases in humans. Dr. Mark Paetzel’s research focuses on the mechanisms by which proteins travel across cell membranes, a process called protein targeting and translocation. Using the technique of X-ray crystallography, Dr. Paetzel is uncovering the three-dimensional structures of the protein complexes that make up the molecular machines involved in bacterial protein targeting and translocation. A better understanding of the functions and mechanisms of these protein complexes may yield insights about how the process works in human cells. In addition, learning how the process differs between bacteria and human cells could lead to a novel class of antibiotics that can shut down protein targeting and translocation activities in bacteria, but leaves human cells unaffected.
Function and mechanism of genomic imprinting on mouse chromosome 6
Along with the completion of the Human Genome Project have come new insights and tools to understand complex gene interactions. Dr. Louis Lefebvre’s work focuses on genomic imprinting, an inheritance process that works counter to the traditional genetic rules. Genes are inherited in two copies – one from the father and one from the mother. Usually, the outcome in the offspring will depend on whether genes are dominant or recessive. With certain genes, however, the inheritance is parent-of-origin-specific: the gene will always be inherited by either the mother or father, with the corresponding gene from the other parent maintained in a silent state. This type of inheritance is thought to be especially important for the development of the embryo and in adult tissues. Defects in imprinting are associated with a variety of disease syndromes. Dr. Lefebvre is studying the mechanisms of genomic imprinting. He hopes to identify new genes required for normal development and better understand the origins and causes of human syndromes that are associated with abnormal imprinting.
Pain in preterm infants
Dr. Ruth Grunau is a world expert on the measurement and long-term consequences of pain in newborns and premature infants in neonatal intensive care units. From the late 1980s, when she conducted landmark research on measures for assessing pain in infants, she has continuously added to the body of research concerning how early pain experiences in very low birthweight infants may affect their clinical and developmental outcomes. Dr. Grunau is conducting several studies on pain and stress in fragile premature infants whose medical care involves repeated exposure to invasive procedures. She is studying how to distinguish pain from stress in very premature infants, and how pain, sedation and analgesia may affect their neurobehavioural development. She is investigating the effects of repetitive pain on attention, behavioural organization and development in very premature infants and toddlers. Finally, she is studying whether positive maternal interaction may moderate the potentially negative effects of neonatal intensive care unit experiences. By learning the most effective ways to minimize any detrimental consequences caused by early repetitive pain and stress, Dr. Grunau’s goal is to help clinicians improve the short- and long-term outcomes of very premature infants.
Airway epithelial injury as a result of corticosteroid-induced apoptosis
In people living with asthma, the cells lining the airway are more sensitive to injury from allergens and other irritants. Researchers have found that these cells have an impaired ability to repair themselves following injury. Dr. Delbert Dorscheid is studying how the inhaled corticosteroids that asthmatics use to control their symptoms may actually contribute to ongoing breathing problems. While corticosteroid benefit asthmatics by suppressing the inflammation of the airway, Dr. Dorscheid’s research has shown that corticosteroid use also causes the death of cells lining the airway. In severe asthmatics, this may create a cycle of repeated injury and incomplete repair that results in permanent damage. Dr. Dorscheid’s is assessing the extent to which corticosteroids may cause permanent damage to airways and also clarifying the mechanisms by which these drugs cause cell death. His goal: the development of treatment options that will have fewer damaging side effects.
Secondary prevention – the gap between evidence and practice
Cardiac disease remains the leading cause of death in Canada. A significant portion of cardiac health care resources are expended on acute interventions such as clot-busting drugs, angioplasty and bypass surgery. However, there is a lack of research on the use of proven strategies – known as secondary prevention – to prevent patients from experiencing subsequent coronary events such as a heart attack. Dr. Karin Humphries is a leading investigator in the area of cardiac health outcomes and the epidemiology of cardiovascular disease. Dr. Humphries is studying how BC patients with heart disease are monitored and how many are using aspirin, beta-blockers and cholesterol-lowering drugs as part of their efforts to reduce their risk of further coronary events. Eventually, she hopes to design a clinical trial to assess new approaches to increase the use of secondary prevention strategies.
Central pathways mediating testosterone effects on hypothalamic responses to stress
The hypothalamic-pituitary-adrenal (HPA) axis is a brain-hormone system that plays an important role in the body’s reaction to stress. The HPA axis controls the secretion of glucocorticoids – steroid hormones that are released from the adrenal glands during stressful episodes. In the short term, acute elevations in circulating glucocorticoids are beneficial, serving to meet the metabolic demands of stress by mobilizing energy stores. In the long term, however, chronic stress-induced elevations in glucocorticoids are implicated in several forms of systemic, neurodegenerative and affective disorders, including depression. Dr. Viau is working to determine the sites and mechanisms by which testosterone acts in the brain to regulate the HPA axis. Given the association of chronic stress with depression and the potency by which testosterone inhibits stress-HPA function, Dr. Viau is investigating where stress, testosterone, and depression intersect in the brain. Dr. Viau hopes his discoveries will be taken from the bench to the bedside, towards implementing sex steroid replacement as an adjunct to antidepressant therapy.
Development and regulation of individual mammalian CNS synapses
A single central neuron can receive signals from up to 50,000 other neurons, which each connect to the central neuron across a synaptic junction. Dr. Timothy Murphy studies individual synapses in the mammalian central nervous system to determine how each contact develops and is regulated. The development and functioning of these individual connections are believed to be building blocks in creating and strengthening the neuronal networks for learning and memory. Dr. Murphy and his colleagues are investigating a number of aspects related to individual synapses. They include: the mechanisms that control the strength of synaptic transmissions at single contacts; the role of calcium in synapse development; the mechanisms that prevent excess calcium from flowing into neurons; and how different types of calcium channels in neurons react to specific and complex patterns of electrical signals in the brain. These basic insights into the behaviour of central nervous system synapses will be important for future diagnostics, as well as therapeutics for diseases of the central nervous system. For example, alterations in synaptic transmission play a role in the origins and treatment of stroke, depression, schizophrenia and epilepsy.
Postsynaptic regulation of neurotransmission
In studying the cellular and molecular mechanisms that allow our brains to learn and remember, Dr. Yu Tian Wang is changing researchers’ understanding of how signals are transmitted throughout the nervous system. Dr. Wang recently came to BC – bringing 12 members of his lab with him – to set up a new laboratory at UBC’s Brain Research Centre and continue his studies on how neurons (brain cells) communicate with one another. Neurons transmit information through a process known as synaptic transmission. Learning, memory and the creation of neural connections in the brain, as well as the development of many brain disorders, are all related to the strength of synaptic transmission. The functioning of neurotransmitter receptors, which are located at the receiving end of synaptic transmissions between neurons, is key to this process. When certain types of receptors, such as glutamate receptors, are understimulated, communication between neurons is decreased and may lead to diseases such as Alzheimer’s; when these receptors are overstimulated, such as during a stroke or epileptic seizure, neurons may die. Dr. Wang’s work has challenged the traditional understanding that the primary way to affect transmission strength between neurons is to increase or decrease the functioning of the receptors. Instead, he has found that some physiological and pharmacological factors, such as certain hormones, can actually alter the number of receptors found on the neuron’s surface and affect transmission strength. This research has many potential applications. For example, enhancing the number of receptors in the brains of people with Alzheimer’s, or in children with neurological disorders, could enhance learning and memory. Decreasing the receptors could protect against brain cell death following a stroke.
Functional interactions between basolateral amygdala and mesocortical dopamine inputs to the medical prefrontal cortex: Electrophysiological and behavioral analyses
As part of a complex, interconnected neural network, the brain’s prefrontal cortex plays an important role in integrating emotional information for complex forms of cognition, such as planning, behavioural flexibility, decision-making and working memory (e.g. remembering a phone number just long enough to write it down). The amygdala — a brain structure residing in the temporal lobe — provides emotional information to the prefrontal cortex. Mesocortical dopamine transmission in the frontal lobes is also important in higher order cognitive processes. Dysfunction of the brain’s emotional and decision-making circuits is believed to be closely linked to diseases such as schizophrenia and drug addiction: patients with these disorders can show structural abnormalities in the prefrontal cortex and the amygdala, decreased levels of cortical dopamine and impairments in emotional processes. Dr. Stanley Floresco is investigating the mechanisms through which emotional and decision-making circuits operate, and how their functioning is modulated by mesocortical dopamine. By shedding light on normal functioning in the brain at a cellular and behavioural level, these studies will increase understanding of the processes that underlie abnormal brain function in many psychiatric diseases.