Young people kill themselves in heartbreaking numbers, and intended and unintended self-injuries are the leading causes of death among our youth. However tragic this is when viewed in the large, the rates of suicide in certain First Nations communities are even higher – in some cases hundreds of times higher – and arguably the highest in the world. I am working to identify both individual and cultural factors that might help reduce the horrendous toll. Previous research has shown a strong link between suicidal behaviours and disruptions in the usual process by which adolescents develop their self-identity. It has also revealed that among First Nations communities, the risk youth run for suicide turns very much on the extent to which different bands have succeeded in reconnecting to their own cultural pasts. My research is directed at understanding the ways cultural differences during the course of identity development help or hinder young people’s ability to insulate themselves from such risks. By understanding the implications of these differences and working out ways of sharing them with various First Nations Communities, it may be possible to assist these communities in reconstructing cultural practices that, once recovered, may serve to better insulate their youth from self-injury and suicide.
Year: 2001
Role for postsynaptic protein complex assembly in synapse development
Neurons (nerve cells) in the brain and central nervous system transmit signals to each other across connections called synapses. Glutamate is the primary neurotransmitter (messenger) that nerve cells use to send signals across these synapses to induce action in the brain. Glutamate enables the brain to develop and language to be learned. Without synapses that allow the chemical signal’s transmission from one nerve cell to the next, nerve cells will not be able to communicate with each other. Other neurotransmitters carry inhibitory signals to reduce activity in the brain. My research has shown that the post-synaptic density protein (PSD-95) stimulates the formation and maturing of the synapses that release glutamate, and increases the release of this neurotransmitter. Members of the PSD-95 family are involved in the development and organization of receptors that are clustered on the receiving side of the synapse. I am investigating how PSD-95 proteins regulate receptor clustering at synapses. This research is important because the number of receptors regulates the strength of the message: the more receptors, the stronger the message. We want to gain a better understanding of how receptors accumulate at synapses, and how changes in this process may underlie long-term changes in synapse structure and function associated with learning and memory. If we can determine how to change the number of receptors, we can permanently enhance the signals received in the brain, which could improve learning and memory function. Also, by understanding how synapses are formed and how neurotransmitter receptor clustering is regulated, we may figure out how to rescue abnormalities in synapse formation and function associated with several neurological diseases such as Alzheimer’s, mental retardation, schizophrenia and epilepsy.
Neurobiological and treatment studies in mood disorders
The treatments currently available for bipolar disorder and major depression are effective in relieving symptoms in only about 70 per cent of the patients. Furthermore, some patients have difficulty tolerating the side effects of these medications. In my lab, we are using Positron Emission Tomography (PET) scans to examine the levels of brain chemicals serotonin and dopamine in people with these mood disorders. Serotonin and dopamine control our emotions, sleep, appetite and energy, all of which are altered in patients with mood disorders. We are studying how these brain chemicals are altered and where changes in the brain occur, so we can develop new treatments that target these areas. Our research to date suggests that one type of serotonin receptor may be important in treating depression. In addition, I have set up a Canadian consortium on bipolar disorder (also known as manic depressive illness), which includes experts on bipolar disorder from all major Canadian universities. The consortium has recently received more than $2 million of funding from the Canadian Institutes of Health Research to examine the optimal length of therapy with novel antipsychotics and the effectiveness of psychotherapy and psychoeducation. We will also be pooling resources to examine how people with bipolar disorder respond to existing treatments compared to their outcomes with new treatments. We will be able to gather extensive data from all the sites to assess the effectiveness of different therapies. Given that many patients with bipolar disorder have problems with memory and concentration, we will study whether these symptoms are part of the illness and if early treatment can diminish them. My goal is to discover what brings on these symptoms and develop new treatments that improve patient outcomes and quality of life.
Analysis of prostate cancer progression using functional genomic approaches
In the early stages of prostate cancer, tumour growth is regulated by male sex hormones, called androgens. In treatment, androgens are removed to shrink the prostate tumour. However, the results of this therapy are usually temporary as surviving tumour cells become independent of androgens for growth and survival. I am investigating the genes responsible for this transition. To analyze these genes in a high throughput manner, I have created a Microarray Facility, the second of its kind in Canada. In the Facility, we can put up to tens of thousands of genes at a time on a single microscope slide. With this technology, we can now do experiments in a few days that would have taken years not long ago. We are comparing normal tissue to early and late tumours, and examining which genes are associated with tumour development. This research will identify the genes that cause prostate cancer, and how genes are turned on and off as the cancer progresses. We can use the information to predict when prostate cancer will occur, prevent its onset and develop new treatments that target the cancer-causing genes. In addition, we are investigating the effects environmental contaminants and dietary factors may have on the development and progression of prostate cancer.
Hepatitis A virus infections among children in British Columbia: Is routine vaccination needed?
Hepatitis A is a viral disease that causes inflammation of the liver. Once contracted, there is no treatment. Adults and older children with the disease usually suffer for four to ten weeks, and the symptoms include jaundice, fatigue, abdominal pain and fever. Young children usually have mild, symptom-free cases that go unrecognized, but can transmit the virus to people of all ages. The BC infection rates for hepatitis A virus have exceeded the national average for more than a decade. Yet a safe, effective vaccine has been available since 1994. The vaccine is currently only given to high-risk groups, and most cases reported by physicians come from these groups. I am investigating the risk of hepatitis A for children in two areas of BC that consistently report high infection rates. The study will determine whether universal childhood immunization is warranted. We can gauge risk for hepatitis A by testing saliva for antibodies to the virus, which would indicate a past infection. Our research team has tested about 800 randomly selected grade nine students. Students also filled out a questionnaire on potential risk factors. We are analyzing this data to identify why the hepatitis A rates may be higher in these areas and whether the scope of the disease is broader than reported cases indicate. If we find high rates of past infection, routine vaccination may be warranted. If low rates are found, the results will provide reassurance that existing sanitary measures are adequate to protect local children.
Gonadotropin-releasing hormone (GnRH) in reproductive biology and medicine
The long-term goal of my research is to understand the multi-faceted role of gonadotropin-releasing hormone (GnRH), the primary regulator of the reproductive process. Our brains release GnRH to the pituitary gland, where it stimulates the synthesis and release of the gonadotropin hormones that regulate gonads (ovaries and testes). My research has shown that GnRH also affects cell function in the ovaries and placenta and the hormone may play a role in controlling estrogen and progesterone production. GnRH has a role in both normal ovarian physiology and in the development of ovarian cancer. Ovarian cancer is a major cause of death, but little is known about the way it develops. We are seeking new knowledge that will help us understand the role of GnRH in the development of ovarian cancer, which should lead to more effective treatments in future. We also know GnRH affects the successful implanting of an embryo to establish a pregnancy and the formation of placenta, but that process is not well understood. My research will help explain the causes and process of fertility. Synthetic GnRH compounds are often used in different areas of reproductive medicine, such as fertility and sterility, ovulation control and assisted reproduction. This research will provide a better understanding of the cellular and molecular effects of these compounds and should improve clinical applications as a result.
Evolution of microbial virulence
There is currently a poor understanding of how a relatively harmless microbe can evolve into one that causes disease. However, analyzing microbial DNA indicates that these bacteria may exchange their DNA with one another, essentially sharing genes that cause disease. Some microbes have evolved into disease-producing organisms relatively recently, making them good models for examining how bacteria results in disease. That’s because we are more likely to relate genetic changes in bacteria to those that cause virulent disease when the changes are more recent. My team is conducting laboratory and computer research to analyze the role gene exchange plays in the development of disease-causing microbes, and to characterize the evolution of recent disease-causing microbes. Understanding how benign bacteria evolved into virulent disease-causing bacteria will increase knowledge of how bacteria cause disease and lead to genuinely new therapeutics and prophylactics to combat current disease-causing microbes, and hopefully help prevent new ones from emerging in the future.
Molecular chaperones and cellular protein folding
I am studying protein folding, a poorly understood but fundamental cellular process by which proteins made in cells fold to attain their correct three-dimensional structures (shapes) and become active. When proteins in a cell do not become active, the result is abnormal function, which often leads to disease. Amino acids are the basic component of proteins, with hundreds of amino acids in each protein. The sequence of amino acids in proteins dictates how a protein folds into its proper shape and achieves its specific function. In some instances, proteins called molecular chaperones have been shown to help newly-made proteins fold properly. My research focuses on understanding how molecular chaperones function at the biochemical and cellular levels, and determining what goes wrong when certain proteins don’t fold properly. For example, one protein called von Hippel-Lindau relies on a particular molecular chaperone to fold correctly. The protein’s loss of function is often caused by protein misfolding, and leads to the major cause of renal cancer. Other diseases, such as Huntington’s and Alzheimer’s, are also associated with the improper folding of proteins. My basic biomedical work on molecular chaperones helps us understand a fundamental process (protein folding) required for good health. Ultimately, such studies may also provide valuable clues regarding how to tackle some diseases that arise from protein misfolding.
Encapsulation based in vitro selection of RNA catalysts
Naturally occurring cellular components such as enzymes are often the only tools available to perform biological research, a limitation that slows the pace of research and hinders the search for cures to human disease. The situation is similar to having your car break down in the middle of the street and having to make repairs using parts scavenged from neighbouring automobiles. A proper toolbox would greatly decrease the time required to perform the repair. My research examines the potential functions of ribonucleic acid (RNA), a cellular component which is vital for the development and functioning of all living things. I am examining the ability of RNA to replicate itself, without the help of protein, because RNA may be capable of important metabolic functions that are currently performed by protein enzymes. I am developing in vitro (in the test tube) techniques to isolate new RNA catalytic molecules. Because these artificially manufactured catalysts perform specific functions, they can be used as tools for conducting medical research. Ultimately, I will examine whether artificial RNA sequences can interact with existing cellular components. Such experiments give us a better understanding of natural processes within cells, perhaps leading to potent new genetic therapies for the treatment of disease.
Environment-sensing ribozymes and DNA-based sensors for biomedical utility
DNA and RNA (the genetic matter in the cells of all living organisms) have properties beyond their function as storehouses of genetic information. I am examining ways we can exploit these other properties to develop new biomedical applications to combat disease. For example, DNA has a slight tendency to conduct electricity. I am investigating how to harness this conductivity to generate sensors that can detect and monitor hormones, metabolites (substances essential to metabolism), toxins, enzymes, drugs, proteins and other molecules in the blood or other body fluids. DNA has potential as an electrical tool to manipulate products at the molecular level. A major interest of mine is based on the discovery that synthetic enzymes made out of DNA and RNA can sometimes function as efficiently as naturally occurring enzymes. Enzymes act as catalysts to accelerate chemical reactions and cellular processes in the body, such as breaking down food during the digestive process. With huge, synthetic DNA and RNA libraries available, we have endless opportunities to create enzymes that perform specific therapeutic functions. Ultimately, we hope to synthesize nucleic acid enzymes to help counteract cancers and viral infections.