While early detection is key to the successful treatment of many types of cancer, tumours still often go undetected and untreated until they are well advanced. Using information generated by the cancer genomics project at the BC Cancer Agency’s Genome Sciences Centre, Dr. Greg Vatcher’s research focuses on gene expression analysis-identifying genes that are activated in the earliest stages of cancer. He is hoping gene expression analysis can help detect tumours earlier. He is also conducting work to determine if tests can predict whether a person will develop cancer, based on pre-cancer genetic changes. Greg is bringing together information from multiple genomics projects, including data from the recently-completed Human Genome Project. For example, he’s taking genetic data being gathered on the normal aging process and relating it to his cancer study to determine if there are any common genetic components.
Research Pillar: Biomedical
Modulation of ligand-gated receptors by G protein-coupled receptors
Antipsychotic drugs for the treatment of schizophrenia work by blocking brain receptors for the neurotransmitter dopamine. An unusual interaction has been observed between dopamine receptors and GABAA receptors – another important type of brain receptor that inhibits brain cell activity. While these two receptors belong to two functionally different families of receptor, researchers have found that blocking dopamine receptors also reduces the number of GABAA receptors on the brain cell membrane surface. Dr. Tak Wong is studying the mechanisms by which the two receptors interact. Ultimately, he hopes to identify possible therapeutic targets that will allow better treatments for schizophrenia.
The role of huntingtin interacting proteins (HIPs) in the pathogenesis of Huntington's disease
Huntington disease (HD) is a neurodegenerative disorder that causes uncontrollable movements, impairment in memory and reasoning ability, and alterations in personality. Patients with the disease carry a mutation in the HD gene, which results in an expanded tract of glutamine (an amino acid). The gene product is therefore a mutated form of the HD protein. This expanded tract disrupts the interaction between the HD protein and other proteins that work together to perform essential cell functions. A modified interaction may alter the normal function of any of the interacting proteins, making specific cells vulnerable to premature death. Anat Yanai is studying the cell biology of several HD interacting proteins, including the way they interact with proteins involved in cellular metabolism and the alterations in their normal function as a result of the mutation in the HD gene. The findings will assist in developing therapeutic strategies for Huntington patients, such as inhibitors or activators of these interactions.
Cell therapies for the treatment of hematopoietic malignancies
Though small in numbers, stem cells are responsible for the continued production of blood cells throughout a person’s life. They are also responsible for regenerating the blood-forming system following a bone marrow transplant in people with leukemia and other blood diseases. While blood stem cell transplantation is a promising therapy, its use is currently restricted because researchers have not yet found a way to reproduce these cells in large enough numbers for effective transplantation. Dr. Clayton Smith’s research is devoted to developing a better understanding of blood-forming stem cells so they can be effectively isolated and manipulated. Using leading-edge bioengineering and computer-based technologies, he is systematically exploring how the body’s environment affects stem cell growth, to see if these conditions can be replicated outside the body. He is also studying the function of certain genes that may be important to stem cell growth. Ultimately, he hopes to learn enough about stem cells to be able to grow them in large numbers outside the body for use in blood stem cell transplantation.
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.
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.
Paracrine processes in prostate cancer progression
Prostate cancer is the second leading cause of cancer-related deaths in men. Advanced prostate cancer is often treated with androgen withdrawal therapy, which blocks the growth-promoting effects of androgens (such as testosterone). Unfortunately, the cancer eventually progresses to an androgen-independent state, allowing for tumour growth without androgens. Dr. Michael Cox is studying how prostate tumour cells with neuroendocrine characteristics contribute to the disease’s progression to androgen independence. His research aims to understand how these cells develop within prostate tumours, what effect such cells have on the growth rate of prostate tumours, and how hormones secreted by these cells influence therapeutic resistance and metastatic preferences during disease progression. Dr. Cox is also working to determine the molecular mechanisms by which prostate tumour cells develop genetic mutations and become less susceptible to cancer treatment. He is identifying how tumour cells respond to growth factors in the presence or absence of testosterone and the cellular changes that allow prostate tumour cells to utilize these growth factors to aid development of testosterone independence.