Inflammation is the response of the body to infection or injury, triggered by the release of proteins that initiate inflammation. Amongst these proteins are members of the chemokine family. Chemokines act as biological beacons, guiding the migration of white blood cells (WBC) from blood vessels to the affected tissue. The structure of chemokines is important to their function. One end of the chemokine binds to tissue and vessels to create a path for white blood cells to follow; the other end interacts with a receptor on the surface of the WBC, prompting the release of further inflammatory mediators that spread the inflammatory response. Recruited and activated WBC attempt to isolate and destroy infectious agents and to prevent further damage. WBC – and in particular cells called macrophages – then help resolve the inflammatory response. In chronic inflammation, continual recruitment and activation of macrophages results in excessive production of reactive molecules that cause host tissue damage, as observed in diseases such as rheumatoid arthritis, multiple sclerosis and chronic obstructive pulmonary disease. The apparent deregulation of macrophage movement may be a result of a change in the structure and function of chemokines. Matrix metalloproteinases (MMPs) are a family of enzymes that modulate chemokine activity by cutting off a portion of either end of the chemokine, which keeps it from functioning properly. Amanda Starr is looking at the functional effects of MMP cleavage on chemokines that recruit and activate macrophages, determining whether cut chemokines are more able to attract and activate macrophage-like cells. She is also developing a technique for detection and quantification of both full-length and cut forms of chemokines from tissue samples. Ultimately, this knowledge could lead to more appropriate and directed therapeutics for the treatment of chronic inflammatory diseases.
Program: Trainee
Aging-induced changes in microdomains of vascular smooth muscle lead to alterations in vasomotor function
Cardiovascular diseases are the primary cause of death and disability in Canada, accounting for one-third of all deaths in 2002. Age significantly increases the risk of developing cardiovascular diseases. As our elderly population increases, it is very important to improve our understanding of how and why cardiovascular diseases occur with age. Most cardiovascular diseases are caused by problems with the way our blood vessels work, especially changes in the muscle layer (made of cells called smooth muscle) that surrounds the blood vessels. The calcium level in smooth muscle is critical for proper cell function, allowing the muscles to contract and generate force. Within the cell, the way that internal compartments called organelles are arranged in relation to each other allows high concentrations of calcium to be localized to small pockets of the cell called microdomains. Microdomains are important for smooth muscle cells to function properly, because certain adjacent proteins are only activated by high concentrations of calcium. Disintegration of microdomains leads to the development of various health conditions. Harley Syyong was previously funded by MSFHR for his Master’s research training. He hypothesizes that smooth muscle cells undergo major changes in organelle arrangement as we age – making it difficult or impossible for cells to form calcium microdomains. Furthermore, proteins that generate microdomains may also be affected, including changes in where they are located or how much of the protein is made. Syyong is monitoring different blood vessels across time, identifying changes to organelles and proteins and determining how they affect blood vessel function. He hopes a better understanding of these changes could lead to ways to decrease the effects of aging on blood vessels, alleviating cardiovascular disease in the growing older population.
Novel algorithms for in vitro gene synthesis and gene optimization with applications to therapeutics and health research
In the development of a vaccine against four strains of the human papilloma virus (HPV), of particular note were studies involving innate immune response when genes of the virus were introduced into host cells. It was observed that increased levels of antibodies were produced by inoculation that used synthetic versions of two HPV genes. The application of gene vaccines, not only for cancer immunization, but also to aid the treatment of infectious diseases, is an ongoing and very active area of study. Developing an efficient and reliable method to produce synthetic DNA is a necessary tool for these studies to succeed. Due to the inherent difficulty of creating long strands of DNA, current technologies for gene synthesis use computational methods for design of shorter DNA fragments called oligos (oligonucleotides), which can be reliably synthesized and assembled. However, ensuring a set of oligos will self-assemble correctly into a longer DNA strand is difficult and complex, and previous software programs have failed to solve this issue. Chris Thachuk is a computer scientist who develops synthetic gene design algorithms. He and his colleagues are developing algorithms to successfully assemble long strands of DNA from oligos. These new algorithms outperform the current state-of-the-art and their effectiveness has been demonstrated through computational experiments on a large set of genes. Three average size genes have been produced with the aid of these algorithms. He now intends to build upon this success by extending the algorithms to produce reliable designs for synthesizing long genes and for synthesizing multiple genes in one step. By providing researchers with more advanced algorithms and accurate modeling software for gene synthesis, Thachuk hopes to contribute to new insights for treatment, detection and/or prevention of diseases.
Identification of genetic signatures predictive of progression risks in oral pre-malignant lesions
Squamous cell carcinoma (SCC), a cancer of the epithelium, is the most common human cancer throughout the body. When SCC occurs in the oral cavity, the five-year survival rate is less than 50 per cent. Before SCC develops, pre-malignant changes often become visible to patients or clinicians. While this offers the opportunity for early intervention to prevent the progression to cancer, only 15-20 per cent of oral pre-malignant lesions (OPLs) will progress to invasive carcinomas. Currently, it is not possible to determine which lesions will develop into cancer. It may be possible to predict cancer risk by studying the molecular features of OPLs. The progression to cancer is caused by genetic alterations to cells; some changes are the “driver” genetic alterations that lead to cancer, while others are random genetic changes. Determining the specific genetic events that are associated with progression to cancer would help identify those at greatest risk for cancer. Ivy Tsui is studying the initiating genetic events at the pre-malignant stage to identify genetic markers that can predict whether an OPL will become malignant. To do this, she is studying the molecular mechanisms of oral cancer progression. Using DNA from banked samples, she is assessing DNA alterations across the whole genome of late stage OPLs and tumours. Once she has identified recurring alterations, she will compare them with the genomes of early stage OPLs – both those that are known to have progressed to cancer, and those that did not. Once validated, these genetic markers will used to develop a clinical diagnostic tool. If DNA from a patient’s OPL can be assessed, patients at risk could be treated early and immediately to prevent progression to cancer. The identified genes critical for oral cancer development could also be used to develop therapeutic targets to treat oral cancer patients.
Investigation into the factors mediating embryonic muscle migration in Caenorhaditis elegans
During embryonic development, precursor muscle cells (myoblasts) are generated in one region of the embryo and then dispersed throughout the body. These migrations are controlled by external signals that guide the migrating cells. Previous muscle research has identified genes for muscle differentiation and development, but the important genes regulating muscle cell migrations have are unknown. Muscle cell migration is of particular importance for a new treatment called myoblast transfer therapy, which is being developed to treat muscular dystrophy and hearts damaged by cardiac arrest. The treatment injects healthy myoblasts into the damaged area in order to repair the affected tissue. A key problem in this treatment is that, for both cardiac and muscle tissue, the myoblasts fail to migrate properly and effectively colonize the damaged area. Ryan Viveiros is studying the embryonic development of a small nematode worm called Caenorhabditis elegans. While substantially simpler than humans, these worms also have muscle and share a number of the same genes required for muscle development as mammals. Because the worm embryos develop inside clear eggs, Viveiros can record the developing embryo and watch the cell migrations in real time. Computer software then allows him to follow the cell migrations and determine which cell types are defective. Viveiros will search for the genes that cause improper muscle migration and determine where these genes are turned on in the embryo. In addition to determining the basics of how muscle migration occurs, Viveiros hopes his findings could lead to new insights for improving myoblast transfer therapy. In addition, because this research is also relevant to cell migration in general, his findings may also inform our understanding of how cancer cells migrate (metastasize).
Epigenetically silenced tumour suppressor genes in lung cancer
Lung cancer continues to kill more British Columbians each year than any other cancer. Diagnosis typically occurs late, leaving only toxic chemotherapy and radiotherapy as the treatment options. Medicine needs better ways to screen for lung cancer in high risk individuals, and better ways to treat them if lung cancer is found. Cancer cells have their cellular “brakes” cut, bypassing the checkpoints in normal cells that stop them from dividing too fast. Human DNA has two copies of each of these checkpoint genes, to ensure a backup in case one copy is damaged. In cancer cells, however, both copies are often damaged by two different mechanisms. One copy may be totally removed, and the other may be silenced by a mechanism called DNA methylation. Because cancer cells go to such great lengths to disrupt both copies of the gene, these genes are likely very important to the continued survival of the cancer. Identifying these genes in early cancers could lead to new screening and therapeutic targets. Ian Wilson is jointly funded by MSFHR and the BC Cancer Foundation. He is working to identify these gene targets, using approaches that enable the entire genome of the cancer cell, as well as every gene product of the cancer cell, to be analyzed simultaneously. He is searching for checkpoint genes in the lung cancer genome that are aggressively shut down in the cancer cell, determining the role of these genes in transforming normal cells into malignant ones. The identification of key checkpoint genes will be very useful as screening markers. This could lead to earlier diagnosis of lung cancer and new targets for therapeutic intervention.
SNARE protein properties in schizophrenia
Schizophrenia is a severe psychiatric illness affecting one percent of the general population. Symptoms typically manifest in early adulthood and often have a devastating effect on an individual’s quality of life and functioning in society. The diverse and debilitating symptoms associated with schizophrenia include hallucinations, delusions, dampened emotion and poverty of speech. It has been hypothesized that faulty neuronal function may contribute to these symptoms. Communication between neurons is achieved by neurotransmission at synapses. Because soluble NSF-attachment receptor (SNARE) proteins mediate this process, they are important in neuronal communication and normal brain function. Altered levels of SNARE proteins have been found in patients with schizophrenia. Vilte Barakauskas was funded by MSFHR for her initial PhD work in this area. Based on her previous findings, she hypothesizes that among people with schizophrenia, SNARE proteins function abnormally at the synapse, contributing to the disorder. She is now working to further characterize SNARE proteins in brain tissue, comparing control subjects to those with schizophrenia in order to identify which protein properties are different in the disorder, and how these differences contribute to altered neuronal communication and brain function. Comparison of protein properties between control subjects and those with schizophrenia may suggest a specific molecular mechanism contributing to altered neurotransmission. This new knowledge could lead to novel treatment targets for this devastating psychiatric disorder.
Short term heart rate variability as an index of nociception
The brain perceives pain through the nociception system, which prompts increased activity in the autonomic nervous system (ANS). In turn, the ANS activates the sympathetic nervous system (SNS), creating a stress response in the body that includes increased respiration, blood pressure and heart rate. In sick patients, a strong stress response can cause serious injury. Anesthesiologists try to minimize the stress response during surgery by giving patients drugs that block nociception. Finding the appropriate balance can be challenging — too much anesthesia can make the patient very ill, while too little anesthesia increases the stress response. Anesthesiologists currently rely on a patient’s vital signs — pulse rate, blood pressure, temperature, and respiratory rate — to estimate the level of ANS activation and determine appropriate drug dosage. Unfortunately, these vital signs alone are not enough to estimate ANS activity, because they are often affected by other factors. Christopher Brouse is developing a nociception monitor that automatically determines the level of activation of a patient’s ANS. It will use computer algorithms that analyze very small, fast changes in the patient’s heart rate, called heart rate variability (HRV). Previous research has shown that HRV responds to ANS activation much more predictably than other vital signs do; therefore, HRV can provide a better estimate. With the data gathered from his first pilot pain study, Brouse is now developing and fine tuning a pain index that correlates with ANS activity. By accurately monitoring subtle vital signs, the nociception monitor has the potential to increase patient safety during and after surgery and reduce recovery times. It could also be used for patients recovering from surgery to gauge their pain and respond with the appropriate amount of drugs.
Is Transcranial Magnetic Stimulation a Useful Clinical Adjunct for Predicting Stroke Occurrence and Severity following Transient Ischemic Attack? A Prospective Cohort Study
Stroke continues to be one of the leading causes of death, long-term adult disability, and illness in Canada. Approximately 1/4 of ischemic strokes are preceded by a brief episode of neurological deficit, or transient ischemic attack (TIA). During a TIA, individuals experience stroke-like symptoms that rapidly disappear. Early stroke risk in patients with TIA is considerable and North American population-based estimates of recurrent stroke range from 9.5% at 90 days, to 14.5% at 1 year. These data highlight the importance of intervention for secondary stroke prevention. However, efforts to estimate stroke risk using clinical profile and diagnostic imaging have shown variable predictive value and validity. Therefore, new markers are needed to help clearly identify high risk individuals and improve current stroke prevention strategies. Jodi Edwards is studying if cortical motor excitability, measured using a brain stimulation technique called Transcranial Magnetic Stimulation (TMS), is a marker of increased stroke risk in individuals with TIA. TMS provides information about the activity of different types of neurons in the brain and with this research, she will determine if there is an association between altered thresholds of intracortical inhibition in the cortical hemisphere affected by TIA and stroke occurrence. In addition, she is also investigating if larger asymmetries in intracortical thresholds are predictive of increased clinical severity in stroke subsequent to TIA. This research has the potential to significantly advance the understanding of the mechanisms underlying TIA and provide a new technique for the identification of high-risk patients following a TIA. Ultimately, this study has the potential to improve stroke prevention strategies and reduce recurrent stroke risk in patients with TIA.
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.