Role of ionotropic glutamate receptors in ischemic injury and dendritic spine dynamics

Inadequate blood supply (ischemia), resulting in neuronal cell death caused by stroke, cardiac arrest or profound hypotension is a leading cause of death and permanent disability. Brain damage resulting from ischemic injury typically manifests as the immediate loss of neurons within the ischemic core, surrounded by a region of brain tissue exposed to reduced blood flow and oxygen called the penumbra or peri-infarct region. This peri-infarct region has been the target of therapeutic protection following ischemic insult (e.g. stroke), and is thought to play a potentially critical role in functional recovery following stroke. Although the precise mechanisms of underlying delayed neuronal cell death are multi-faceted, the over-activation of N-methyl-D-spartate receptors (NMDARs), is known to have a key role in mediating neuronal injury in both in vitro and in vivo models of stroke and traumatic brain injury. Dr. Allen Chan is examining the role of selective NMDAR activation and blockade on dendritic spine dynamics immediately following a focal ischemic stroke, with the aid of established pharmacological treatments and in vivo brain imaging techniques. Dendritic spines are hypothesized to be key structural substrates within the penumbra that mediate plasticity changes necessary for functional recovery after stroke. Dr. Chan’s project will increase our understanding of the mechanisms and pathology of stroke injury with respect to the damage and death caused to pivotal brain cell connections called synapses, and ways to potentially alleviate this damage and death. In so doing, rescue and protection of damaged but repairable parts of the brain may lead to treatments that enhance functional recovery and therapies that directly impact patient health and quality of life.

Influence of aging on candidate neuropsychiatric disease genes measured using differential coexpression

Aging and developmental change represent body wide changes in genes. Because many genes change as people age, the relationships between genes also often change, a phenomenon called differential coexpression (of RNA levels). Studying differential coexpression has uncovered changes that cause disease. However, knowledge gaps remain with respect to relationships between disease and aging in neurological diseases, for example. Many diseases have a specific age of onset, schizophrenia for example, typically strikes in early adulthood. This suggests that in multi-gene disorders, where interactions between genes play a role, rewiring may occur between susceptibility genes at the age of disease onset. Dr. Gillis’s current research project builds on his earlier work which showed that aging is associated with numerous changes in coexpression, and that genes known to be associated with specific diseases change their relationships with age in healthy individuals. His current project involves studying how the relationships between candidate genes – differential coexpression – in schizophrenia and Alzheimer’s Disease, change as a function of age. By understanding how networks of gene interactions might be rewired in diseases, we can identify candidate genes that would be missed otherwise, and beneficially influence the design of treatments and diagnostics.

Cataloguing Chromosome Instability Mutants: Implications for Cell Biology, Cancer and Therapeutics

The accumulation of mutations in the DNA of human cells can lead to tumour formation. More than 80 percent of solid tumours exhibit chromosome instability (CIN) – the property that results in an unequal distribution of DNA to each daughter cell upon cell division. The genetic instability associated with these tumours may allow them to adapt quickly and remain in the body.

Dr. Peter Stirling's research is focused on generating a comprehensive database of genetic mutations that lead to CIN, using the Baker's yeast cell model. The results will then be translated to related human genes. Using yeast to identify candidate human CIN genes has already been successful for a handful of genes and Dr. Stirling's project will extend this effort. The candidate CIN genes identified will provide important insight into the biology underlying tumour formation. Further, the results will validate interesting CIN genes relevant to cancer in human cells and provide greater understanding regarding the mechanisms of CIN for those genes.

Additionally, Dr. Stirling is also working to identify secondary genes whose mutations cause cell death in combination with a CIN mutation. By validating these "synthetic lethal mutant gene combinations" in human cells, Dr. Stirling will have defined drug targets for tumours carrying mutations in a particular CIN gene. And, working in collaboration with researchers at the University of British Columbia, Dr. Stirling will identify small molecules (i.e. drugs,) that selectively kill tumour cells based on the identified second-site mutations. Overall, the results will reveal new aspects of tumour biology, identify new anti-cancer drug targets and contribute to the development of new anti-cancer drugs.

Neural Mechanisms of Reward Learning and Cognitive Control in Children with Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity Disorder (ADHD), is characterized by its behavioural manifestations including difficulties with attention, hyperactivity and impulsivity. It is one of the most common childhood disorders with a prevalence rate of three to seven percent of school-aged children. ADHD carries a significant impact not only on children diagnosed with this disorder, but also on their families, schools, communities and the health care system. Numerous theories of ADHD have focused on deficits in executive functions, specifically cognitive control and the inability to inhibit inappropriate behaviours. Neuropsychological and neuroimaging studies in children with ADHD support a theory of frontal-subcortical dysfunction: specifically, a dysfunction in the midbrain dopamine (DA) system that may result in an impaired midbrain DA system and reinforcement learning, or the ability to learn to modify behaviour on the basis of rewarding and punishing stimuli in the environment. Furthermore, recent developments in reinforcement learning theory indicate that the midbrain DA system carries Reward Prediction Error (RPE) signals. Carmen Lukie is investigating how a midbrain DA system for reinforcement learning may be impaired in children with ADHD. This study follows on from her earlier research which showed that children with ADHD are particularly sensitive to the saliency of rewards. Specifically, she found that RPE signals in children with ADHD are modulated by the context in which feedback is given, and differs from what is observed in typically developing children. The current study will replicate this finding, while correcting for the limitations of the earlier study. Ultimately, the results of this research could lead to the development of novel, more effective behavioural and pharmacological treatments. Further, the research may expand to include individuals with substance abuse, pathological gambling, conduct and borderline personality disorders.

The role of Apical Junction Complex in airway epithelial repair and differentiation in asthma

Asthma is a serious global health problem, affecting over 300 million people worldwide. The disease is predominantly an inflammatory disorder of the conducting airways, and can be treated or controlled using current therapies. However, un-controlled asthma leads to continual inflammation and damage, resulting in permanent scaring which is termed airway remodeling. Airway remodeling can be defined as changes in the composition, content and organization of cellular and molecular constituents of the conducting airways. One of the structural changes that occurs as a result of airway remodeling is detachment of the cells that line the surface of the airways, called the epithelium. In normal airways, the epithelium forms a barrier against the inhaled external environment which includes aero allergens, viruses and particulate matter, through the formation of apical junction complexes (AJCs). In asthma, part of the abnormal response to inhaled allergens is thought to be due to impaired barrier function caused by damage to the airway epithelium and loss of AJCs. Emerging evidence suggests that AJCs are able to influence other aspects of epithelial function such as release of inflammatory mediators and mechanisms of epithelial repair. Building on earlier work in this area, Dr. Tillie-Louise Hackett’s current research is designed to determine whether AJCs play an important role in normal airway epithelial repair and if the mechanisms involved are altered in asthmatic patients. The results of her research will provide scientists and clinicians with a better understanding of the pathological mechanisms that contribute to multiple respiratory diseases. In addition, Dr. Hackett’s findings will open avenues for the development of new therapeutics to improve the lung health of Canadians living with obstructive lung diseases, such as asthma and Chronic Obstructive Pulmonary Disorder.

Congenital Migraine Mutations alter the Calcium-Dependent Regulation of P/Q-type Calcium Channels and Affect Synaptic Plasticity

Migraine headaches affect approximately 15 percent of the Western population. However, the complicated genetic and underlying physiological basis of migraine has resulted in both slow advancement in new treatments and poor understanding of the disease at the cellular level. Familial Hemiplegic Migraine (FHM) is a type of migraine with similar clinical features to typical migraine, and likely with similar cellular mechanisms, but with well-understood genetics. FHM has become a leading model for studying typical migraine. FHM is clinically characterized by migraine headaches, usually preceded by visual or auditory auras (sensations), and accompanied by hemiparesis (one side of the patients body undergoes varying degrees of paralysis during the migraine attacks). The migraine symptoms can last from a few minutes to several days. Approximately 50 percent of patients with FHM have mutations in the CACNA1A gene, which codes for a type of calcium channel protein that is primarily responsible for facilitating communication between neurons in the brain. Paul Adams’ research focuses on identifying FHM genetic mutations in patients and then introducing those mutations into cloned calcium channel genes. The effects of the FHM mutation on calcium channel properties can then be studied by introducing the mutated channel into a human cell line and then studying the channel using electrical recording techniques. Additionally, the effects of FHM mutations on communication between neurons in the living brain will be studied in mice that have been genetically engineered to contain human FHM mutations in their CACNA1A gene. The results of Adams’ research will provide a better understanding of the molecular mechanisms behind FHM, and thereby contribute to the development of more effective therapies for all types of migraine headaches.

Identifying biomarkers associated with the diagnosis and illness progression of mood disorders

Despite decades of extensive genetic and pharmacological research, the pathophysiology of Bipolar disorder (BD) remains elusive. Consequently, a growing number of studies are focusing on the molecular biology underlying BD, and some consistencies with respect to possible mechanisms of action have emerged, including: (1) altered cerebral energy metabolism; (2) decreased expression of the mitochondrial electron transport chain (mETC), complexes I-V subunits in prefrontal cortex, hippocampus and lymphocytes; (3) increased protein oxidation in the prefrontal cortex and serum; (4) higher levels of lipid peroxidation in the cingulte cortex and serum; (5) increased levels of DNA oxidative damage in hippocampus and lymphocytes; (6) alteration in the balance between anti-inflammatory/ pro-inflammatory cytokines; and (7) decreased levels of brain derived neurotrophic factor (BDNF) in the hippocampus and serum. These findings highlight the fact that oxidative damage and neurotrophic factors are present in both the brain and periphery, and suggest that oxidative stress and BDNF could be potential biomarkers for mood disorder. Dr. Ana Andreazza is working as part of a collaborative network in Canada, Brazil, Australia and Portugal, that is studying a large sample size of patients with mood disorders (bipolar disorder and depression), in order to determine whether mitochondrial dysfunction, oxidative stress markers, cytokines and BDNF levels may be used as biomarkers of progressive illness. As a secondary objective of their studies, Dr. Andreazza and colleagues will correlate their findings on the oxidative stress with cognitive impairment, accelerated aging (i.e. telomere shortening), and decreased levels of neurotrophic factors. In addition to identifying biomarkers that may be used to follow progressive illness, the results of this work may represent significant therapeutic targets. In the larger picture, the discovery of biomarkers for mood disorders and their incorporation into clinical decision-making could dramatically change the future of mental health care.

Bayesian Adjustment for Unmeasured Environmental Confounding

Studies in environmental epidemiology are often concerned with understanding the health effects of environmental exposure in various forms. Because these studies are, by nature, observational, it is often difficult to make valid statistical conclusions. Additional complications arise from the presence of confounding variables, which relate to both the exposure and health effect, and hence complicate the relationship. Traditionally these confounders are controlled for by including them as explanatory variables in a statistical model. Bias-free conclusions become much more difficult, however, when some confounders are unmeasured or inadequately measured. A wide variety of environmental epidemiology studies have suffered from this problem, including, for instance, estimating the association between air pollution and mortality, between magnesium levels in drinking water and mortality from acute myocardial infarction, and between ethnicity, income and limiting long-term illness. The focus of Luke Bornn’s research is the development of a coherent, unified framework for modeling environmental risk exposure in the presence of unmeasured confounding. His model will account for spatial dependencies between adjacent geographical groups as well as other factors that are important for these studies, such as ecological bias and pure specification bias. His hypothesis is that by accounting for spatial dependence and unmeasured confounding under a comprehensive and unified framework, the risk estimates will more accurately estimate the true exposure risk and provide more appropriate estimates of the corresponding uncertainty. By developing a model through simulations, analytic results and application to real data sets, Mr. Bornn’s research will create a model that is both practical and useable for environmental epidemiology practitioners.

Understanding the influence of early childhood sexual trauma and resiliency on health outcomes among young Aboriginal people who use drugs in British Columbia

Recent research has determined that young Aboriginal people who have been sexually abused and who use drugs are at greater risk of several negative health outcomes including Human Immunodeficiency Virus (HIV), infection. It is now well recognized that building resiliency is fundamental to the success of traditional Aboriginal health care practices and that cultural buffers may moderate vulnerability. There are a number of aspects to building resilience including attending to the mind, the body, the emotions and the spirit and, notably, there may be gender and age-related differences in resilience dynamics. Consequently, focused research is required to develop practical theories of resiliency and targeted interventions that will address trauma and facilitate stress coping among Aboriginal young people. To that end, Margo Pearce is investigating specific questions about the role that historical trauma and protective factors have with respect to vulnerability to HIV and hepatitis C (HCV) among young Aboriginal people in BC. She is utilizing existing data from the Cedar Project, an ongoing initiative funded by the Canadian Institutes of Health Research that monitors HIV and HCV risk among 600-1000 young indigenous people aged 14-30 who use injection and non-injection drugs. She is analyzing gender differences in health outcomes over time related to early childhood trauma amongst the Project participants. Ms. Pearce’s work will provide a better understanding of the protective factors that prevent specific adverse health outcomes among young Aboriginal men and women. Furthermore, it will address trauma and protective factors from a global public health policy perspective.

Perceptual and attentional abnormalities in autism – understanding impaired discrimination of the eyes

Autism is a pervasive developmental disorder involving impairments in social interaction, verbal and non-verbal communication, a lack of imaginative play, and repetitive and restricted solitary activities. A critical goal of autism research is the identification of biological, behavioural and cognitive markers that will help researchers determine the links between genes and autism and aid in the development of effective diagnostic tools, as well as improve upon existing intervention and treatment programs. Of note, abnormal perceptual processing is currently a candidate marker of autism. There is mounting evidence to suggest that people with autism show specific perceptual abnormalities, and that these abnormalities may play a causal role in deficits in social processing. For example, research suggests that individuals with autism show abnormal perception of faces, with a reduced ability to discriminate visual changes to the eye area of a face, as compared with normal perception of changes to the nose and mouth. However, it is unclear whether these abnormalities are due to a deficit in perceiving visual information from the eyes, or a lack of attention to this visual information. Elina Birmingham’s research involves the use of eye tracking and a new methodology called the moving window technique, to measure the focus of attention in children with autism while they undertake visual face exploration. Her research will provide insight into several key questions regarding perceptual and attentional abnormalities as indicators of autism in children. The results of her study will contribute to the goal of identifying markers of autism, and as such may have important implications for treatment and intervention methods.