In order to combat neurological disease and mental illness, a greater understanding of how the brain functions at the molecular and cellular level is needed. If we can learn how nerve cells form connections during development, we can develop therapies for regenerating connections following injury. Dr. Ann Marie Craig is leading an effort to understand how nerve cells form and modify synaptic connections. Her group uses a combination of fluorescence imaging, molecular biology, and electrophysiology to investigate how nerve cells communicate. By studying nerve cells growing in a dish, the scientists have already begun to identify molecular signals on the surface of nerve cells that induce contacting partners to form a synaptic connection. Mutations in one of these molecular cues has recently been linked to autism. Dr. Craig and her team are also studying how neurotransmitter receptors are localized and modified to control the strength of synaptic signaling between nerve cells. Given that synapses are the basic units of communication in the brain, the knowledge gained from understanding synapse development and modification has broad implications for the treatment of all neurological diseases and mental illnesses.
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Structural studies of clinically-relevant protein-carbohydrate interactions
Thanks to new scientific methods, including use of high-speed computers, the search for ways to diagnose, treat and cure disease has changed greatly in the last 50 years. While chance discoveries are still important, new technology allows researchers to systematically probe the molecular nature of disease-causing organisms and the medicines being developed to treat them. X-ray crystallography is a technique to determine the three-dimensional structure of crystallized molecules. Dr. Stephen Evans is using the technique to study the interactions between proteins (such as antibodies and enzymes) with carbohydrates to learn about the atomic structure of these molecules. In one project Dr. Evans is investigating the antibodies responsible for inherited immunity to learn how the body reacts to new and emerging diseases. In another project he is investigating how a protein molecule can mimic a carbohydrate and be used to vaccinate patients against their own cancer. He is also examining how enzymes can be used to make new carbohydrates that can, in turn, be used as new medicines. Finally, Dr. Evans is developing a new version of his SETOR molecular graphics software that will enable researchers to reduce complicated molecular structures to simplified illustrations.
Bringing evidence to the patient
Asthma is becoming more common throughout the world. It is a major cause of hospitalization and an avoidable cause of death in a minority of patients. Dr. Mark FitzGerald, who has taken a leading role in developing national and international asthma guidelines, is evaluating new treatment strategies for asthma. These include drug therapies and strategies specifically designed for patients with near fatal asthma (NFA). In collaboration with other researchers, Dr. FitzGerald is also assessing how variations in asthma management affect outcomes. Tuberculosis (TB) is a global health problem that affects high risk groups in Canada, such as injection drug users and Aboriginal persons. Currently there is no way to determine an individual’s risk of developing active TB when the disease is latent, unless there are other risk factors such as HIV or diabetes. In collaboration with the Centers for Disease Control and Prevention in Atlanta, Georgia, Dr. FitzGerald is researching how to better identify those at risk of developing TB and investigating better strategies for the treatment and the prevention of TB. In the area of outcomes-related research, Dr. FitzGerald is the Director of the Centre for Clinical Epidemiology and Evaluation where he coordinates a multi-disciplinary group of investigators interested in the development, implementation and evaluation of evidence based interventions.
Molecular Basis of Campylobacter jejuni Infection
Campylobacter jejuni (C. jejuni) is the leading cause of bacterial food poisoning worldwide, infecting approximately 300,000 Canadians, three million Americans, and even higher numbers in developing countries each year. Most cases result from eating contaminated poultry; other causes include exposure to young animals and drinking contaminated water or milk. The bacteria cause severe bloody diarrhea, vomiting and fever, and can lead to more serious medical problems such as bowel disease, arthritis and paralysis. Compared to well-studied bacteria like E. coli and Salmonella, relatively little is known about how C. jejuni causes disease. Using new genetic tools, Dr. Erin Gaynor is identifying and characterizing C. jejuni genes involved in causing infection. She is examining the interaction between the pathogen and host cells to determine how the bacteria cause disease at the molecular level. Dr. Gaynor is also investigating why C. jejuni causes disease in humans when it harmlessly inhabits the intestinal tracts of many other animals, and how host systems respond to infection with the bacteria. This research may lead to a greater understanding of the mechanisms of pathogenesis for C. jejuni and contribute to the development of new treatments and potentially a vaccine to prevent infection from occurring.
Novel statistical methods for inference of associations between traits and SNP haplotypes in the presence of uncertain haplotype phase
A single gene can be solely responsible for certain genetic disorders. For example, only people who carry two defective copies of the CFTR gene develop cystic fibrosis. By contrast, complex genetic disorders such as cancer and diabetes likely involve a number of genes that increase susceptibility, and act in conjunction with lifestyle and environmental exposures to increase risk for developing disease. Most success in identifying single causative genes has been achieved by studying co-segregation of a trait with genomic regions in families. However, to tackle complex disorders, researchers have turned from family studies to population studies that investigate associations between a disease and variations in DNA sequences known as single nucleotide polymorphisms (SNPs). Blocks of SNPs, known as haplotypes, offer promise for identifying genes contributing to disease risk. For example, SNP haplotypes were used to help identify a predisposing gene for Crohn’s disease. The underlying idea is that similarity among haplotypes of affected individuals will lead to disease associations. Dr. Jinko Graham is developing improved biostatistical methods that account for haplotype uncertainty in analyzing these disease associations. The new techniques will eliminate inaccuracies associated with previous methods and could enable researchers to better evaluate genetic and environmental risks for conditions including diabetes, cancer and cardiovascular disease.
An in vivo model of abnormal neuronal circuit formation: the role of glutamatergic synaptic transmission in dendritic arbor growth and synaptogenesis
The causes of many brain diseases, such as epilepsy and schizophrenia, are unknown. Researchers such as Dr. Kurt Haas are exploring the possibilities that abnormal brain development in the prenatal stage may play a role. Using a powerful gene delivery technique, Dr. Haas is investigating how nerve cell activity contributes to brain development, specifically, the effect of altered levels (i.e. too much or too little) of activity on the structure and function of neuronal circuits. This research could lead to more specific and effective interventions to prevent abnormal circuits from forming during prenatal development, and also to treat adults with schizophrenia or epilepsy.
A novel approach to studying DNA copy number variation in schizophrenia and bipolar disorder
Schizophrenia and bipolar disease are severe mental illnesses that affect thinking, mood and behaviour, and cause lifelong disability. Schizophrenia alone costs the Canadian economy about $2.5 billion per year. While the exact causes remain unknown, both disorders are thought to arise from the interaction of genetic defects with environmental factors. Research into these psychotic disorders lags behind advances in other health fields, so new and innovative research strategies are needed. Studies have shown that certain DNA changes can strongly predispose people to psychotic disorders, but the full scope of DNA changes in schizophrenia and bipolar disease has not been explored. Dr. Robert Holt is using new technology called microarray comparative genome hybridization to scan the entire genome of patients with schizophrenia and bipolar disease to detect losses or gains of DNA. The research could contribute to better understanding of the genetic factors that predispose people to schizophrenia and bipolar disorder, lead to diagnostic tests to identify those at risk, and strategies for early intervention to achieve better outcomes.
Shaping the outcome of viral-mediated autoimmune myocarditis
Coxsackievirus infections can cause a variety of illnesses, including heart disease. In North America, the coxsackievirus is estimated to cause up to 30 percent of new cases of dilated cardiomyopathy, a condition in which the heart becomes enlarged and pumps less strongly. Dr. Marc Horwitz is studying how viruses such as coxsackievirus can induce autoimmune diseases such as chronic heart disease, and how immune system components shape and control development of the disease. Studies have shown that the body’s immune response has a profound effect on the development of chronic heart disease after infection with the virus, revealing that immune cells and antibodies that attack infection also damage heart tissues. Dr. Horwitz is examining how innate and adaptive immune responses following viral infection contribute to development of chronic heart disease. He will use findings from the study to design and test new methods to prevent heart disease, which could also lead to new treatments.
The function of ING proteins in S. cerevisiae
Tumour suppressor genes, such as ING1, help regulate normal cell growth by encoding proteins that inhibit abnormal proliferation of cells. Dr. LeAnn Howe is studying the molecular properties and function of ING1 proteins to understand the processes that lead to the development and growth of tumours. Research has linked ING1 proteins to modification of histones, the main protein component of chromatin, which makes up our chromosomes and genes. Evidence suggests that defects in regulation of chromatin structure may improperly activate or silence genes, leading to disease. Dr. Howe is examining the way ING proteins interact with chromatin to determine whether the proteins can modify chromatin. This research could help explain the role of ING1 genes in cancer development and contribute to new cancer therapies.
The early external cephalic version 2 trial
Of almost 40,000 babies born in BC in 2002, nearly 2,000 (4.8 percent) were breech (their bottom and legs were born before their heads). Research shows that breech babies are most safely delivered by Caesarean section. However, Caesareans cause more complications than vaginal births, and the resulting scar on the uterus complicates subsequent pregnancies. When a baby is found to be in a breech position using ultrasound, care providers can try to turn a baby to a head down position by feeling the baby through the mother’s abdomen and moving the baby’s head downward and its bottom upward. This procedure is called external cephalic version (ECV), and studies have shown that the chance of both breech birth and Caesarean section is reduced if ECV is performed close to the end of pregnancy (after 37 weeks). Dr. Eileen Hutton and her team of researchers from across Canada are conducting The Early ECV 2 Trial, which is an international randomised controlled trial designed to investigate whether performing ECV earlier in pregnancy, at 34-35 weeks, further decreases the number of Caesarean sections without increasing the risk of preterm birth. Dr. Hutton, founder and editor of the Canadian Midwifery Journal of Research and Practice, is also involved in a large international trial investigating the best way for twins to be born (vaginally or by Caesarean section), and is doing work in BC investigating patient initiated Caesarean section.