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.
Year: 2004
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.
Intracellular calcium stores as master regulators of pancreatic beta-cell survival: studies on transplantable human islets and knockout mice
Canada has a growing diabetes epidemic, which costs the Canadian health care system an estimated $13 billion annually. More than two million Canadians have the disease, and by 2010, the number is expected to increase to three million. Diabetes is also a major health problem worldwide. Although diabetes can be treated with insulin, a cure for this devastating disease remains elusive. All forms of diabetes are associated with the loss of functional pancreatic islet cells. However, very little is known about the underlying factors controlling how and why pancreatic islet cells die. Dr. James Johnson recently discovered important networks of molecules that control survival of islet cells. For example, one such network includes the RyR2 protein, which controls the release of calcium in the cell, and the calpain protein, which can split other proteins in response to increased calcium. Dr. Johnson is comparing the role of this survival network to other molecular networks to investigate how pancreatic islet cells die. The research could lead to better therapies for diabetes, including more successful pancreatic islet transplantation, a promising experimental treatment that depends critically on the continued survival of the donated cells. The findings could also improve understanding of other diseases where calcium is involved in cell death, such as heart failure, Alzheimer’s disease and stroke.
Studies on rational treatment of Parkinson's disease
Parkinson’s disease is a chronic, progressive disorder that affects about 100,000 Canadians, at an annual cost of more than $2.5 billion. The disease involves loss of both brain cells and chemicals that modulate communications between brain cells – causing not only motor symptoms of tremor, stiffness, and slow movements but also cognitive and behavioural changes. Conventional drug therapy for Parkinson’s disease replaces dopamine in the brain. Although most motor deficits usually improve after therapy, more than 50 percent of patients (particularly those in the later stages of the disease) may develop difficult problems, such as involuntary movements, dementia and psychosis. Dr. Chong Lee is studying neural mechanisms of these complications, which are resulting from the disease itself or the chronic use of Parkinson’s drugs. Dr. Lee is also evaluating the effectiveness of neuro-protective treatment, a strategy to prolong the survival of injured cells and slow the progression of Parkinson’s disease. He ultimately aims to develop strategies to treat dementia and behavioural symptoms of the disease and to reduce or prevent treatment-induced complications in patients with Parkinson’s disease.