Asthma is the most common chronic disease in children. It affects eight to 10 per cent of the population in developed countries, and rates are increasing. Susceptibility to asthma and other allergic diseases runs in families, which indicates that genes influence its development. However, numerous studies examining the influence of changes in the genetic code have led to inconsistent results. A possible explanation for the inconsistency is a failure to account for epigenetics. This emerging field of study involves investigating the basis of inherited traits that affect how genes function without affecting the sequence of the underlying genetic code. The airway lining cells, or epithelium, are a promising cell type in which to identify novel mechanisms of asthma. Jian-Qing He is studying cultured airway epithelial cells from 150 asthmatic and non-asthmatic children to explore whether a combination of genetic and epigenetic changes in immunity-related genes are central to the development of childhood asthma. Results from this study will allow for a better understanding of how genetic and epigenetic differences in epithelial cells are related to the development of asthma. Potentially, such knowledge could contribute to the development of more effective methods of screening for susceptibility to asthma and better preventive strategies.
Year: 2007
The excitatory and inhibitory synaptic balance in neurodevelopmental disorders: the role of neuroligins
Neurodevelopmental disorders result from gaps, delays or variations in the way a child’s brain develops, often interfering with learning, behaviour and adaptability. Research has shown that neurodevelopmental disorders have a strong genetic basis, yet the genes involved have not been clearly identified. The onset of disorders such as autism, fragile-x and Rett syndrome occurs after neurons have developed, during the time connections between neurons (synapses) are being formed to facilitate transmission of signals from one neuron to another. These disorders may, therefore, result from altered synapse formation and maintenance. Some of the genes thought to be associated with these disorders produce proteins involved in synapse formation and maintenance. Alterations in the size, form and structure of synaptic components have been demonstrated in fragile-x syndrome, Rett syndrome and autistic spectrum disorders. This suggests that these diseases are associated with abnormal or halted synaptic development and maturation. Building on her MSFHR-funded Master’s research, Rochelle Hines is studying specific proteins involved in synapse formation and maintenance to assess whether and how they contribute to the development of neurodevelopmental disorders.
The medical management of human intersex: An evaluation of parent-clinician communication about treatment options
The surgical and hormonal management of intersexed children is a much more common component of pediatric care in Canada than many people realize. Intersex conditions, where noticeably atypical genitalia is deemed to require intervention, occurs in about 1:2000 live births. In the international context, driven by an increasingly well-organized coalition of intersexed people, the potentially harmful effects of these medical interventions are being debated. Proponents of standard treatment protocols justify genital surgeries with an in-the-best-interest-of-the-child rationale, claiming that to leave a child’s body in a state of sex ambiguity would inevitably lead to psychological harm and sexual maladjustment. Yet, no long-term follow up studies have been conducted to substantiate this claim. The delivery of current medical services is not structured in ways that allow for follow-up with intersexed adults, and much of the evidence from intersexed people themselves suggests that, in the long-term, the best interests of intersexed children are not protected. Many grow into adulthood feeling stigmatized and traumatized, and are left in both physiological and psychological pain by their years of medical treatment. Rodney Hunt is conducting a detailed qualitative study of parent-clinician communication to gain insight into the ways in which the current medical management of intersexed children is taken up or contested in a clinical setting. He aims to achieve a deeper understanding of the institutional and social factors that influence parent-clinician communication and decision-making when treatment options are discussed. Ultimately, Rodney’s goal is to advance current theoretical understandings of sex and gender in medicine and health policy frameworks, and to provide a valuable evidentiary base for diverse stakeholders, including clinicians, social scientists, health policy makers, intersex support groups, women’s health advocates, and those most directly affected, intersexed people and their families.
Elucidating the function of Bardet-Biedl Syndrome (BBS) proteins in Intraflagellar Transport (IFT)
Cilia are fine, hairlike projections that protrude from most cells of the human body. Many of these cilia perform sensory roles such as detecting light, sensing temperature and perceiving smell. Dysfunction of cilia is implicated in a number of conditions, most notably polycystic kidney disease. The less common Bardet-Biedl Syndrome (BBS) reflects the effects of complete loss of cilia function throughout the body. Patients with this condition suffer from obesity, polydactyly (more than 20 fingers/toes), cystic kidneys, infertility and many other conditions. Analysis of cilia structures in a tiny worm called nematode Caenorhabditis elegans has provided tremendous insight into the function of BBS proteins. Research has revealed that BBS proteins are involved in the process of intraflagellar transport (IFT), the dynamic mechanism through which cilia are built and maintained. An absence of BBS proteins appears to impair cilia function, apparently by causing the IFT machinery to split apart, although other deficiencies are highly likely. Peter Inglis has developed a new approach in studying the interaction of BBS proteins within the IFT complex, focusing on how BBS proteins are involved in the rearrangement of core IFT proteins. He will dissect BBS function and assemble a general model for the role of BBS proteins in IFT. Ultimately, his work promises to shed significant light on a cellular mechanism implicated in a wide variety of human disorders.
Person Perception in Individuals with Autism Spectrum Disorders
Autism has increased 700 per cent in the last decade. The developmental disorder is characterized by severe difficulties with social interaction and communication, an extremely limited range of activities and interests, and often by the presence of repetitive behaviors. A recent study showed autism spectrum disorders (ASD) are the most costly of all childhood disorders in terms of prevalence, outcome, response to treatment, economic cost and family stress. The ability to recognize and understand the constantly-fluctuating emotional expressions of the human face and their associated mental states usually develops in the first year of life. Research has shown that these abilities are seriously impaired in individuals with autism. The causes of this impairment are not yet understood, and although researchers have put forward a variety of explanations, there has been no definitive answer. Based on her past research, Lisa Jefferies is implementing a new approach to the study of person perception in individuals with low to severe autism spectrum disorder and a milder variant known as Asperger’s Syndrome. Jefferies’ approach is based on computer-generated, human-like “”talking heads”” that allow each component of an expression to be controlled and manipulated independently. She aims to use this tool to understand the root of face-perception deficits in children with autism. Jefferies also believes the talking heads will provide an ideal format for an intervention technique, as they could be programmed to focus on critical combinations of facial actions. Her ultimate goal is to develop new knowledge that will contribute to the design of more effective intervention and training to improve the social intelligence of individuals diagnosed with ASD.
Quantitative Three-Dimensional Assessment of Bone and Cartilage in Osteoarthritic and Normal Knees Using Novel Imaging Methods and Mechanical Indentation Testing
Osteoarthritis (OA) is a painful, debilitating disease affecting approximately three million Canadians, most commonly at the knee. In addition to joint cartilage damage, the disease is also marked by changes in the underlying bone. It has been suggested that changes in bone stiffness, thickness and density influence and accelerate the breakdown of cartilage and the development of OA. In order to verify this (i.e. understand when during the disease process these changes occur and assess their impact on the timing and extent of damage to the bone or cartilage) there is an urgent need to develop a tool that can reliably assess bone and cartilage simultaneously. The aim of James Johnston’s research is to understand early onset and progression of osteoarthritis and to develop diagnostic tools for its early detection. Johnston has already developed a novel method of matching bone to cartilage that can be used to assess cartilage and underlying bone simultaneously in any joint. He is now working on a method to investigate relationships between bone (thickness, density) and cartilage (thickness, biochemistry) using magnetic resonance imaging (MRI), computed tomography (CT) and three-dimensional assessments. He will then link information gained through these imaging methods with physical stiffness measures to determine how these properties are affected at early and late stages of OA, compared to healthy subjects. This research will improve understanding of how OA develops, and contribute to the development of methods for the early detection and treatment of the disease.
Estimating current and future direct medical costs associated with HIV/AIDS in British Columbia using an integrated model of clinical disease history and population transmission dynamics
HIV/AIDS continues to be a major health issue in Canada, twenty-five years after the first cases were reported. About 58,000 Canadians, including 13,000 BC residents, are infected with HIV (the human immunodeficiency virus that leads to AIDS), and the incidence appears to be rising. A rough estimate sets the medical costs of caring for people with HIV/AIDS at more than $800 million a year. But rapid treatment advances make medical costs a moving target. Karissa Johnston is using the computer simulation model she developed in her earlier MSFHR-funded research to more accurately estimate the annual and lifetime medical costs of treating people infected with HIV. Johnston has designed a series of modules to measure the amount of HIV virus in peoples’ bloodstream (called the viral load) over their lifetime, their initiation and adherence to antiretroviral medications, their use of health services, and their survival time with different treatment regimes. As new treatments or data become available, individual modules can be updated without affecting the others. This information can help health care providers assess the costs and effectiveness of different treatment options. For example, antiretroviral medications successfully suppress viral load, reducing the risk of passing the infection during a sexual encounter. Even though the medications are costly, this tool will show if they ultimately result in costs savings due to a reduction in new infections.
Investigation of the Mechanisms of Hematopoietic Cell Generation from Human Embryonic Stem Cells
Human embryonic stem cells (ES cells) — cells obtained from an embryo when they are only a few days old — are unique because they can become any type of cell. They can also multiply in the laboratory for very long periods of time without losing this special ability. ES cells offer huge medical potential, both in research and clinical applications. They could, for example, be turned into cells affected by cancers, such as blood cells or brain cells, then genetically altered to become cancer-like and studied to identify potential drug targets or other unique characteristics. Human ES cells could also be used as a cell source for many different kinds of transplantation. One of the biggest hurdles to overcome in working with human ES cells is increasing understanding of how these cells turn into specific kinds of cells. Because they can become anything, ES cells often become many different things at once, which makes them difficult to study and potentially inappropriate for transplantation. A better understanding of the mechanisms an ES cell uses to turn into different kinds of cells would help ES cell differentiation be better controlled and directed towards cell types of interest. Building on her previous MSFHR-funded research, Melanie Kardel is researching how ES cells turn into blood cells. Kardel’s focus is on determining how many blood cells can be produced from a single ES cell, and what genes can influence either the number of blood cells produced or how long it takes to produce them. The research could contribute to more standard, controlled procedures for high efficiency blood cell production from human ES cells.
The molecular characterization of murine hematopoietic stem cell self-renewal divisions
Every day, billions of new blood cells are produced in the human body. The origin of these cells, which are produced in the bone marrow, can be traced back to a tiny population of self-maintaining cells known as blood stem cells. Drugs used in current cancer treatments cause considerable damage to these stem cells and this can prevent more effective doses from being used for treating a number of cancers. Better ways to protect blood stem cells or to increase their numbers in a controlled fashion are needed. Additionally, many types of leukemia are known to be sustained by mutated blood stem cells. More detailed understanding of the mechanisms that regulate normal blood stem cells and how they become mutated is needed to determine how leukemia arises and how the many types of the disease can be treated more effectively. David Kent and his colleagues have recently developed a technique that allows them to isolate nearly pure populations of normal blood stem cells from the many different cell types (blood stem cells are at a frequency of between 1 in 10,000 and 1 in 15,000 cells) present in the bone marrow of adult mice. They are now able to stimulate these cells to behave differently (i.e.: to give rise to a daughter stem cell or not) in short term cell culture using different growth factors. Kent is comparing the sets of genes in these purified and differentially manipulated blood stem cell populations to identify genes that are involved in the regulation of normal blood stem cell expansion. He hopes his work will facilitate further research into the controlled expansion of stem cells and other blood cell types, and offer insight into the mechanisms by which stem cells mutate and replicate as cancer cells. He also hopes to expand fundamental knowledge of stem cells as a potential source of treatments for multiple cancers.
Characterizing novel transcripts enriched in human embryonic stem cell lines
Human embryonic stem cells were successfully cultured in a lab for the first time in 1998. Scientists believe that transplanting these cells holds great promise for treating injury and disease because they have the unique ability to replicate themselves indefinitely and develop into a wide variety of other types of cells. But a number of challenges have to be tackled before stem cells can be safely used in the treatment of patients. These include understanding and being able to control how stem cells are transformed into other types of cells, overcoming immune rejection in patients receiving transplanted cells, and understanding any links between stem cells and the origin of cancer. Jaswinder Khattra is tackling a related challenge: defining the activity of novel genes and proteins in stem cells. Although thousands of human genes are known, many remain uncharacterized. Khattra is investigating the properties of novel genes discovered in stem cells to define how they act within the cells, and whether they play a role in controlling how stem cells differentiate into other cells. This research also examines the proteins produced by these genes and how they interact in regulating cell growth and function. Improved understanding of the molecular structure and function of these genes and proteins could contribute to improvements in cell-based therapies and drug screening for a range of diseases.