Population health research seeks to develop a better understanding of how social, cultural, environmental, occupational and economic factors determine health status. While most population health research focuses on specific hypotheses, understanding the bigger picture can yield insights on a larger scale. How socio-economic factors influence or correlate with health status, how diseases group together in constellations, and how these relate to health services usage, medication usage and health-driven outcomes are all important questions. Cluster analysis (CA) is a class of statistical techniques that can be applied to data that exhibit natural patterns. However, current CA methods are poorly suited to broad population health data, which may contain hundreds of variables with many dimensions. The result is that patterns between classes of variables can be lost in the statistical “noise.” Eric Sayre is developing a new method of CA called Cluster Analysis for High-Dimensionality Data (CAHDD), which provides a means for filtering statistical noise, and allowing important patterns to emerge from the data. By applying CAHDD to Canadian population health data, Eric’s research seeks to answer big-picture questions about socio-economic factors and health status. CAHDD will be available for other health researchers to interpret population health data, leading to significant advances in our understanding of the determinants of health status in our population.
Research Location: Simon Fraser University
ACK family tyrosine kinase may participate in the control of dorsal closure through negative regulation of Egfr
The Rho family of small GTPases in the fruit fly Drosophila are key controllers of cell shape and cell movement through their participation in signalling networks that control a variety of cellular processes. These proteins function as molecular “switches”, turning on or off the particular steps in the signal pathways to control cell shape or cell movement. The study of these molecules provides us with important medical insight since disturbance of their signalling has been implicated in a variety of disorders including cancer and a number of inherited conditions, such as mental retardation, deafness and facial deformities. These proteins have also been shown to be key regulators in wound healing. The activated Cdc42 kinases (ACKs) are proteins shown to be effectors for the Rho GTPases Cdc42, and are linked to the regulation of Drosophila Dorsal Closure (DC). DC is a well-known animal model system for studying wound healing. Previous studies have demonstrated Drosophila activated Cdc42 kinase (DACK) functions in controlling cell shape change and movement of epidermal cells during DC. Weiping Shen is using the DC as a model system to assemble signalling networks controlling the movement and shape of cells. The learning gained from these signalling pathways will shed light on their roles in human development and disease. By developing a better understanding of the mechanisms that allow signals to translate into physical movements, this research could lead ultimately to solving many genetic and developmental puzzles related to human diseases.
Improved Biostatistical Methods to Detect Gene-by-Environment Interaction in Case Control Association Studies
Complex genetic diseases are thought to result from genetic susceptibility factors acting in conjunction with environmental, lifestyle or non-genetic factors such as infectious, chemical, physical, nutritional and behavioural exposures. In the past, researchers have used the case-control study design to investigate disease associations with non-genetic factors. Recently, new genetic information in the form of Single Nucleotide Polymorphisms (SNPs) has been integrated into these population health studies in an attempt to better understand the joint effects of non-genetic and genetic risk factors. However, conventional statistical methods for this study design are not powerful enough to detect such joint effects, even for studies with very large sample sizes. Jihyung Shin is developing new biostatistical methods to more efficiently extract information from case-control data about statistical interactions between genetic and non-genetic risk factors for disease. By developing extensions of the methodology to allow for missing information on genetic risk factors in a statistically valid way, her work can accommodate the analysis of disease associations with SNP haplotypes, which are combinations of genetic variants at several nearby SNPs on the same chromosome. This type of analysis can offer improved power over analysis of single SNPs for detecting the effects of genetic factors and their interactions with non-genetic risk factors. The ability to identify interactions between genes and non-genetic factors that affect the risks of complex genetic disorders will improve our understanding of disease pathogenesis and help with the development of more effective and appropriate treatments, prevention and screening tools.
New RNAs Phenotypes from Old by Random Recombination and Selection
The emergence of new viral species or strains by evolution is viewed as a great potential danger to human health. Besides mutation, recombination (shuffling of genes) plays an important role in the evolution of viruses – such as HIV or Hepatitis E. There is significant concern that more dangerous viral strains or species may evolve through recombination. However, the complexity of virus-host systems makes the study of this process very difficult. Using a new method she developed, Qing (Sunny) Wang is using ribozymes (specific functional RNAs) as a model for studying the mechanisms of random recombination in viruses. She hopes that this work will shed more light on how viruses evolve through recombination.
Understanding social competence in Autism Spectrum Disorders: The development of a standardized measure
Autism and its related disorders are commonly described as lying along a continuum that ranges from mild to severe. As a whole, these disorders are often referred to as Autism Spectrum Disorders (ASD). ASD describes individuals who have three main areas of difficulty: communication and language; social interactions; and restricted or repetitive behaviours/interests. Although social difficulties represent the primary problem for higher functioning youth with ASD, there is a lack of standardized measures to assess the nature and severity of their social impairment. In British Columbia, it is particularly important that clinicians have access to standardized and psychometrically sound tools because ASD diagnoses are tied to publicly-funded services. Jodi Yager is developing and validating a measure of social competence that will be appropriate for use with higher functioning individuals with ASD. She anticipates this tool will ultimately be useful to mental health professionals in both clinical practice and research. Jodi’s standardized measure may play a role in assisting with important assessment and diagnostic procedures and in evaluating the effectiveness of interventions and programs (e.g. social skills training). In addition, by providing a detailed assessment of social strengths and weaknesses, this measure could prove helpful in treatment planning, such as recommending services and interventions that are specifically tailored to meet an individual’s needs. By improving our understanding and measurement of social functioning in youth with ASD, Jodi’s research will contribute to improving developmental outcomes and quality of life in this population.
Structural and functional characterization of the vibrio cholerae toxin-coregulated pilus
Vibrio cholerae is a bacteria that infects the human small intestine to cause the potentially fatal diarrheal disease cholera. This disease, which is spread through contaminated drinking water, represents a major health threat in developing countries, with young children being most vulnerable. The toxin co-regulated pili (TCP) on the surface of V. cholerae are important components in the bacteria’s ability to cause disease in the host. TCP are hairlike filaments that hold the bacteria together in aggregates or microcolonies, protecting them from the host immune response and concentrating the toxin they secrete. The TCP are also the route through which the V. cholerae bacteria is itself infected by a virus called CTX-phi, which enables V. cholerae to produce cholera toxin. Dr. Lisa Craig is determining the molecular structure of the TCP and delineating the regions of this filament that are involved in microcolony formation and in binding to CTX-phi. The information obtained from her studies may lead to vaccines, therapeutics and diagnostics for combating this deadly disease.
Algorithms for RNA structural interaction prediction and antisense RNA design
Until recently, RNA was only considered to be a carrier of information from DNA to proteins. Because the functional roles of RNAs were largely unknown, their structural properties received limited attention. However, with the recent discovery of regulatory RNAs – RNAs that control the activity of genes – interest in the functionality of RNA has surged. Understanding their structure is a key starting point in determining how RNA molecules function. Dr. Cenk Sahinalp is using new approaches to increase the reliability of his previously-developed mathematical frameworks and corresponding algorithms for accurately predicting individual RNA structure and the joint structure of interacting RNA molecules. This includes the development of algorithms for designing RNAs that help regulate the expression of select genes. His long term goal is to help inform the development of artificial RNAs that might be used as therapies for disease.
Developing and using inhibitors to examine the role of O-GlcNac post-translational modification of proteins on glucohomeostasis and beta-cell adaptation
Type 2 diabetes develops when our bodies are unable to properly regulate blood glucose levels. Normally, blood glucose levels are carefully maintained at optimal levels through the finely-orchestrated action of pancreatic beta cells, as well as insulin-responsive tissues. These tissues must be able to sense and rapidly respond to changes in glucose levels; when this system is disrupted, type 2 diabetes develops. Researchers know that glucose is central in regulating insulin synthesis and secretion, but how this occurs remains only partly understood. Dr. David Vocadlo is studying the role of a single sugar unit known as O-GIcNAc, which is installed by the enzyme OGTase and removed by the enzyme O-GlcNAcase, that is believed to act as a glucose sensing mechanism that triggers cells to adapt to their nutrient environment. While this mechanism is generally seen as an important process in maintaining health, disruption of this process can lead to extended periods of abnormal O-GIcNAc levels, and may cause some diabetes-related health problems. By developing and using inhibitors of both the O-GlcNAcase and OGTase enzymes, how O-GIcNAc acts in nutrient sensing will be addressed. Dr. Vocadlo’s research may prove useful in correcting problems in glucose sensing among type 2 diabetes patients.
A dynamic structural description of the cyclic nucleotide receptor region of pacemaker ion channels
Rhythmic electrical impulses that drive beating of the heart and sleep waves in the brain are controlled by natural pacemakers called ion channels. Pacemaker channels act as electrical switches, and they switch on faster when they bind natural chemical messenger molecules called cyclic nucleotides (CNs). This is thought to involve temporary structural changes in the region of the channel molecule that interacts with the CNs. By modifying the structure of the CN-binding region in the channel and observing how this affects switching, Dr. Edgar Young is studying what structural features of the channels help or hinder this process. Gaining a better understanding of the structural changes that allow switching may lead to the development of new drugs to control pacemaker acceleration, which could alleviate problems such as accelerated heartbeats or epileptic seizures.
The role of RNA in the evolution of life
One of the fundamental issues facing biology is the question of our origins. Despite the fact that time and evolution have erased much information about early life on earth, a number of fascinating clues remain within cells that have led to the proposal of an “RNA world” hypothesis – the premise that RNA (ribonucleic acid) was once the dominant biological catalyst, capable of important metabolic functions that are currently performed by protein enzymes. Dr. Peter Unrau is exploring the chemical versatility and evolutionary potential of RNA. He has been examining the ability of RNA to replicate independent of protein. Along with his chemical interests in RNA, he is also exploring the processing of RNA by eukaryotes (cells with a distinct membrane-bound nucleus) and studying the interaction of small RNA processing and viral replication in plants and humans.