Computational simulation of transcription factor binding for the prediction of regulatory regions in DNA sequences

The regulation of when and where a gene is turned on (gene expression) is a complex process, fundamental to how a cell behaves and interacts with the environment around it. Abnormal changes in gene regulation are associated with many diseases, including cancer, asthma, and obesity. One class of proteins involved in the regulation of genes are transcription factors (TFs). TFs recognize and bind to short sequences of DNA near the genes they regulate and act to increase or decrease the expression of their target gene. The binding interaction between TF proteins and DNA is affected by an array of biophysical factors in the cell nucleus, making this complicated process a good candidate for computational modelling through bioinformatics. Bioinformatics is a relatively new field in which computational approaches are used to study biological problems; a field that unites computer science, statistics and the life sciences. Rebecca Hunt Newbury is developing a software simulator to model the TF binding process in a dynamic, interactive setting, with the intent of predicting the locations in a DNA sequence at which TFs will bind and regulate genes. From there, she will begin to incorporate the spatial relationships and combinatorial interactions between TFs that result in the different expression responses of genes. Hunt Newbury’s research will contribute to clearly defining the regions of DNA that participate in regulating a gene. Her work may ultimately contribute to new approaches for combating diseases caused by abnormal gene regulation.

The mechanism of U4/U6 Di-small nuclear ribonucleoprotein formation: a modification/interference analysis

Proteins, the molecules that carry out many cellular functions, are synthesized according to information contained in DNA sequences. Converting information from DNA into a protein requires an intermediate step in which the DNA sequence is copied into a molecule called RNA. In humans there is an essential biochemical process called RNA splicing, in which non-coding portions of the sequence are removed and the remaining protein-coding portions are joined together to form a template for protein synthesis. Ninety percent of human genes are subject to splicing, so it is not surprising that errors in this process have been linked to a wide array of diseases, including retinitis pigmentosa, spinal muscular atrophy, cystic fibrosis, myotonic dystrophy, Alzheimer’s disease and cancer. Splicing is catalyzed by the spliceosome, a large and dynamic complex that consists primarily of five small nuclear ribonucleoproteins (snRNPs) designated U1, U2, U4, U5, and U6. During spliceosome assembly, the snRNPs interact with each other in a step-wise, ordered way. One of the first steps in assembly involves U4 and U6 pairing to form a particle called the U4/U6 di-snRNP. Although the di-snRNP complex is essential for spliceosome assembly and function, the mechanism by which it forms is poorly understood. Tara Wong is investigating the process by which U4 and U6 undergo essential conformational changes necessary for spliceosome assembly. She is using chemical modification/interference experiments to determine how free U4 and free U6 snRNPs interact to form the U4/U6 di-snRNP. This knowledge will be fundamental to understanding spliceosome assembly and function, and should ultimately lead to a better understanding, and treatment of splicing related diseases.

Stress-hormone production and health: the importance of forgiveness

When they are functioning well, intimate relationships contribute to better health and increased longevity. A cornerstone of well-functioning relationships is the ability to forgive a partner for relationship transgressions, such as telling lies, flirting with another person, or saying hurtful things. Repairing a relationship following the hurtful actions of one partner has consequences, not only for relationship quality, but also for physical health. One way that the act of forgiveness may be associated with health relates to cortisol production. Cortisol is a hormone released by the adrenal gland during times of stress. Chronic elevations of cortisol have negative effects on cardiovascular, immune, and brain systems and potentially increase the risk for diabetes, hypertension, immune system deficiency, and other illnesses. Being unforgiving has been shown to produce cortisol in a similar pattern to that which is experienced during other stress responses. Kim Watt is examining whether cortisol production is a mechanism for the link between forgiveness and general physical health. She is conducting her study with 200 newlywed couples, recording their physical health and measuring their cortisol levels at baseline and following a set of emotionally stressful marital discussions. Results from this study will contribute to a clearer understanding of the risk pathways by which negative relationship processes may lead to poor physical health. This may suggest that a focus on strengthening close relationships by improving couples’ skills when discussing relationship issues is a way of ultimately reducing health problems.

Making Outreach Matter: Exploring Interventions and Decision-Making for Two Intravenous Drug User Populations in Vancouver’s Downtown Eastside

Within the intravenous drug user (IDU) population of Vancouver’s Downtown Eastside (DTES), female commercial sex workers and Aboriginal women are overrepresented. These two groups are especially vulnerable to unique sets of health and social challenges that may be related to their substance dependency, including increased susceptibility to sexually transmitted infections, physical violence, psychological trauma and malnutrition. Their social challenges can include increased contact with law enforcement, lower education, unemployment and inability to access community support. The needs of these two groups both intersect and diverge based on a series of factors. There are currently numerous services and interventions that target intravenous drug using women, including emergency mental health counselling, addictions treatment and recovery, harm reduction (both for IDU and commercial sex work) and general support groups. However, the rates of use of these services by commercial sex workers and Aboriginal women are relatively low. This suggests that many women either choose not to or cannot make use of the available health services and interventions. In order for these interventions to effectively help these two groups of women in coping with deeply interconnected health and social challenges, these factors must be investigated, addressed and understood within a complex matrix. Ashley White is conducting an in-depth study to explore the characteristics, perceptions of health services, and needs of commercial sex workers and Aboriginal women practising intravenous drug use. Her findings will provide essential insight into potential ways that health planners can offer accessible services that better meet the requirements of these women.

Role of beta-cell ryanodine receptors in diabetes

Type 2 diabetes, or diabetes mellitus, is a growing epidemic and a major health problem worldwide. In Canada, the prevalence of diabetes in the general population is around five per cent, but rates as high as 40 per cent have been reported for some indigenous groups. Diabetes can cause serious health problems, including kidney failure, heart disease, stroke and blindness – costing Canada’s health system more than $13 billion annually. It is known that diabetes results from a progressive loss of functional insulin-releasing pancreatic beta-cells. Research evidence suggests that reduced beta-cell survival may be a critical event in this process. The mechanisms underlying beta-cell death in diabetes remain unresolved, but it is becoming increasingly evident that intracellular calcium signals play a vital role in most known types of cell death. Dr. Dan Luciani is examining the role of the ryanodine receptor (RyR), a calcium handling protein, in the death of pancreatic beta-cells. His recent work with colleagues has demonstrated that the flux through these calcium channels regulates beta-cell survival in culture. Using mouse models, he now intends to determine if defects in RyR signaling may predispose to diabetes by testing what happens to beta-cells’ ability to control blood sugar levels when RyR is missing. These studies will lead to a better understanding of the molecular mechanisms that regulate the function and available mass of insulin secreting beta-cells. Ultimately, this knowledge may lead to novel strategies for the treatment, and eventually cure, of this increasingly prevalent disease.

Peripheral neurophysiological basis of sensorimotor deficits in individuals with essential tremor

Essential tremor (ET) is a neurological disorder characterized by shaking of the hands (and sometimes other parts of the body) that occurs with voluntary movement. Often mistaken for Parkinson’s disease, it is the most common tremor disorder. Approximately 75 per cent of people living with ET experience some limitation in their activities, and these limitations typically get worse with increasing age. Therapies for essential tremor focus on tremor reducing medications, but effective treatments remain limited. Consequently, new insights into disease mechanisms are needed to guide the development of more effective therapies. The origins of essential tremor are believed to involve abnormal rhythmic activity in the brain, which then travels down to the peripheral nervous system. However, the specific neural pathways that the tremor travels, as well as how ET influences the recruitment of muscles for movement, remains unclear. Also unknown is the impact of tremor on sensory receptors found within skeletal muscles, which provide the sense of position and movement of the limbs. Dr. Martin Héroux is conducting studies on British Columbians with ET to determine how their muscles and sensory receptors are affected by abnormal rhythmic activities of essential tremor. He hopes these studies will increase our knowledge of the neural mechanisms involved in the generation of essential tremor and provide a better understanding of the motor-sensory deficits associated with tremor disorders. Ultimately, this knowledge could contribute to the development of more effective anti-tremor therapies.

Extraction and evaluation of transcription factor gene-disease association

Genes are the basic blueprints used by the cells in our body. When a gene is modified, the cells in our body can be affected; in the worst case, this can cause a disease. A researcher can often be faced with several candidate genes to study in relation to a particular disease, and choosing the genes with the best potential for discovery is important for making the best use of research resources. Around the world, researchers are studying thousands of different genes to understand their roles in health and disease states. Their findings – in the form of abstracts and annotations – are captured in a variety of databases. However, this vast source of biomedical literature is an under-utilized resource. Powerful computational biology methods are required to allow researchers to mine this information. Warren Cheung is developing an automated system that can examine the available biomedical literature and quantitatively determine which genes are most likely involved in a particular disease. Not only will the system identify previous relevant findings, its integration of data and annotations from many studies is expected to identify previously unknown associations between genes and diseases. Cheung’s research will initially focus on the involvement of transcription factor genes in brain diseases and cancer. However, the techniques developed and tested will be easily adaptable to all types of genes and diseases. Cheung’s award is jointly funded by MSFHR and the Down Syndrome Research Foundation. With the ability to automatically look at all the papers that have been published on genes and their functions, this system will make unbiased predictions and previously unknown linkages. This promises to be a powerful tool for understanding genes and disease.

Investigating the molecular mechanisms of micrometastasis and tumour dormancy in pediatric sarcoma

Sarcomas are an aggressive type of childhood cancer arising from bone or soft tissue. Despite advances in cancer treatment, sarcomas remain a deadly disease because of their tendency to spread throughout the body (metastasis). Following cancer surgery to remove a malignancy, remnant sarcoma cells are often able to remain dormant in the body for months or years, in spite of efforts to eradicate them with chemotherapy. When such therapies are ineffective, these hibernating cells may revive and regrow as deadly metastases. Under laboratory conditions, cultured cancer cells are able to survive for long periods in the form of multi-cellular clusters called “”spheroids””. Interestingly, these spheroids also appear to enter a hibernation state, with cancer cells trading away their ability to grow rapidly in favour of the ability to survive for long periods. The cells use their “oncogenes” to suppress the expression of their growth-promoting genes, despite the fact that oncogenes are normally known for their cancer-promoting properties. It is believed that cancer cells and their oncogenes target a new set of genes to drive this hibernation. Tony Ng is screening all human genes for ones important in maintaining this hibernation. Using a technique called gene expression profiling, he will determine which genes become more active when cancer cells hibernate. He is also studying two genes, TXNIP and YB-1, which appear to be important for spheroid survival and dormancy. Laboratory results will be validated using clinical samples of dormant tumour cells from childhood cancers. Ng hopes that the genes identified in these studies will become the basis of chemotherapies to specifically kill these hibernating cells, resulting in therapies that are more effective and less toxic to patients.

The role of active participation in the development of perspective taking in children with and without autism

Autism and its related disorders are characterized by widespread abnormalities of social interactions and communication, as well as severely restricted interests and repetitive behaviours. These disorders are described as lying on a continuum of severity, referred to as the autism spectrum, reflecting the diversity of symptoms in children with autism. Studies indicate that one major commonality among children on the autism spectrum is an impairment in their understanding of other people’s perspective or point of view. This ability is seen as the major underlying process in children’s overall social functioning. Newly-developed theories of how children typically develop perspective taking have provided important insights for assisting children with autism to improve their social understanding. However, while intervention programs are aimed at improving children’s social competence through increasing their ability to understand someone else’s point of view, the underlying mechanisms and effects on children’s ability to reason about other people’s perspectives are not well researched. Theo Elfers is investigating how perspective-taking develops by focusing on a specific aspect of social cognition — the role of children’s active engagement in perspective-taking tasks. Studying both children with and without autism, Elfers is giving the children structured tasks that allow the child to take both perspectives in a social exchange (e.g., gift giver and gift receiver), while allotting enough time for the child to remember each perspective and prompting the child to anticipate the other’s perspective. Ultimately, this work should provide researchers and mental health professionals with insights into how perspective-taking develops, and also increase the effectiveness of future training programs aimed at fostering social competence in children on the autism spectrum.

Spatial epidemiology of trauma: understanding and preventing injury through geographic analysis

Over the course of the last two decades, the notion that health and well-being is tied to societal and environmental circumstances that may overlap and intersect with important elements of individual experiences has been widely utilized as a means of characterizing the inequitable distribution of a wide range of health outcomes, including injuries. Importantly, the population health perspective model is transforming how we understand the complex interaction between the environment and injuries, and tailoring prevention and policy responses to address the inequitable distribution of their occurrence. Yet, there are currently no frameworks in place for how we quantify the interconnectivity between social, environmental, and geographical determinants of injury and building evidence that highlights the underlying relationship between all three factors with injuries. Addressing the ecological and geographical questions regarding this complex interaction entails integrating the current injury prevention models with the tools and analysis functions of geographic information systems (GIS). GIS are widely recognized as essential tools in public health promotion and surveillance as they allow for the integration of multiple data sources and the visual and spatial analysis of health data in relation to locations, distances, or proximities. GIS can increase our understanding of current population access to emergency medical services, the extent that injuries ‘cluster’ in certain areas and among certain population groups, as well as help researchers better understand and locate the links between people and their environments that may either reduce or increase injury risk. Nathaniel is currently applying GIS in a number of research areas in order to determine where important systems elements might be augmented to improve population access to critical care, for identifying incidence patterns that might have gone under noticed had they not been examined using GIS, as well as how this technology might be used to help researchers more accurately target prevention efforts to reach communities in-need. This research will help structure ongoing injury prevention efforts in British Columbia as well as provide future researchers with a number of frameworks for using GIS to improve our understanding of the societal, environmental, and geographic factors associated with injury.