The majority of cells in the body contain a microscopic, hair-like organelle projecting from the cell surface called a cilium. Cilia play roles in motility and sensory signalling. In many cells, the disassembly of cilia by the cell is a precursor to mitosis (cell division) and cilia are reassembled by the cell following mitosis. Dysfunction of this structure and process leads to a variety of conditions, including blindness, infertility and polycystic kidney disease. MSFHR funded Moe Mahjoub in 2003 to complete his PhD study of cilia. His previous work showed that the kinase Fa2p is implicated in the regulation of ciliary shedding and assembly, as well as in cell division. He has determined that Fa2p is dynamic, moving to different locations in the cell at different points in the ciliary and cell life cycle. Moe is now working to discover exactly how Fa2p exerts its effects. He hopes his research will provide key insights into the mechanism of various human diseases.
Program: Trainee
Bayesian propensity score analysis for pharmacoepidemiologic research
Data on prescription claims, health services provided, and hospital discharges are routinely collected in the Canadian health care system for the management of health services. This information is valuable for observational research assessing the effectiveness and safety of drug therapies, allowing more rapid and cost-effective investigations. In addition to yielding large sample sizes with long periods of follow up, they also better reflect the spectrum of medical practice in large populations compared to randomized clinical trials. However, because study participants are not randomly assigned to treatment and control groups through this methodology, findings may be biased if there is inadequate control of the variables. There is a need for new statistical tools to analyze healthcare administrative data. Lawrence McCandless is developing and investigating a new statistical method called a Bayesian propensity score analysis. Through computer simulations, mathematical techniques and models for drug prescribing patterns, the Bayesian analysis will improve the validity of observational investigations of the effectiveness and safety of drugs using large health care administrative databases.
Perfectionism and Social Rejection in the Development of Eating Disorder Symptoms
The causes of eating disorders are complex, yet a number of factors have emerged that may put individuals at increased risk for developing these disorders. These include social factors, such as social exclusion and personality traits, such as perfectionism. With support from a 2003 MSFHR Trainee Award, Brandy McGee studied how perfectionism combines with cultural influences, such as physical ideals suggested in advertisements, to cause eating disorders. Brandy is now exploring how multidimensional perfectionism interacts with experiences of social exclusion to produce eating disturbances. She is testing the hypothesis that social rejection will lead to an upswing in eating disturbances (such as binge eating, thoughts about food, negative mood, etc.) in individuals with high levels of social dimensions of perfectionism, but not in women with low levels of perfectionism. The outcomes of this study will help us better understand how social factors shape health status and enable us to better predict who is at risk for eating problems, and to intervene earlier to promote health.
An adaptive intensity modulated radiation therapy (IMRT) technique through complete on-line treatment plan modification
Radiation therapy uses high energy, penetrating radiation to destroy or stop development of cancer cells, a process which also causes damage to surrounding healthy tissue. Conventional radiation treatment is created using a planning software that generates a plan based on the patient’s internal geometry (position of the target cancer cells and surrounding organs), and this plan remains unchanged for the whole treatment process. The ability to more closely and uniformly target the cancer cells, which includes the ability to map and adjust to changes in the internal geometry between and during treatments, would help to minimize impact to surrounding healthy tissue. A new form of radiation therapy known as adaptive radiation therapy (ART) may hold the answer. This modality allows for modifications of the original treatment plan before each treatment fraction, while the patient is in the treatment room. However, due to time constraints, only a selected set of treatment parameters of the original plan can be modified, which limits the full potential of this technique. Ante Mestrovic is exploring the development of a method for rapid, complete treatment plan modification that characterizes the patient’s internal geometry using three-dimensional ray tracing. His goal is to develop a time-efficient way of adapting treatment plans immediately before each treatment session. This would provide for more precise targeting of cancer cells, helping to reduce radiation exposure to healthy tissue and surrounding organs and contributing to a better outcome for patients undergoing radiation therapy.
Characterizing the role of sumoylation at the budding yeast kinetochore
Aneuploidy – the result of the uneven separation of two matching sets of chromosomes during cell division – is found in more than 70 per cent of cancers and is now widely accepted as a major predisposing condition to cancer initiation and progression. Benjamen Montpetit is studying the role of the kinetochore, a protein complex that is of fundamental importance to the equal separation of chromosomes during cell division. Using yeast cells as a model, his research into the components responsible for chromosome transmission will result in a better understanding of the events involved in creating aneuploid cells and will provide a mechanistic basis for understanding chromsome instability in human cancers.
Cell fate mapping of putative neural stem cells
Disease states such as Alzheimer’s, Parkinson’s, stroke and spinal cord injury each affect the nervous system in what was once thought to be an irreversible manner. However, recent scientific evidence suggests that damaged areas of the nervous system may have their functions restored by transplantation of neural stem cells or by administration of molecules that coax the body’s neural stem cells to self-repair. To put this knowledge into practice, researchers require a better understanding of the basic mechanisms of stem cell development. Barbara Murdoch was previously funded by MSFHR to identify proteins specific to the surface of neural stem cells so she can study their growth requirements. Building on this, she is now using olfactory epithelium cells to determine the role of the protein nestin in the development of neural stem cells. She is studying which cell types express (produce) nestin and determining their pattern of expression. By understanding these mechanisms, she hopes to contribute key knowledge necessary for effective clinical applications requiring stem cell transplantation, expansion and gene or drug therapies.
Involvement of inducible nitric oxide synthase and nitrosative stress in vascular dysfunction in Diabetes
Cardiovascular complications are the major cause of morbidity and mortality in diabetes – a disease that affects millions of people worldwide. The lack of specific treatments for these complications is due, in part, to the poor understanding of the underlying cellular and molecular mechanisms, e.g., the signalling pathways that might cause malfunction, and pathways that protect normal vascular function. In diabetes, there are changes in the ability of blood vessels to constrict and relax, which in turn can affect blood flow and blood pressure. Prabhakara Nagareddy is studying how blood vessels function in diabetes and the mechanisms directly relevant to the development of vascular disease. He is exploring the vasoconstrictory role of a well-known growth receptor (epidermal growth factor receptor) pathway and the vasodilatory inducible nitric oxide synthase (iNOS) pathway in normal and diabetic arteries. By developing an understanding of how these pathways produce their effects, this research could facilitate the discovery of unique drug targets for future cardiovascular disease treatments, particularly for high blood pressure.
The role of Annexin II in airway epithelial wound repair and the effect of corticosteroids on the Annexin II regulated pathway
Asthma is an inflammatory condition of the lungs that affects a growing number of individuals in developed countries worldwide. Current research and therapies for asthma are aimed at relieving the symptoms associated with the disease rather than the underlying defect. In spite of the use of anti-inflammatory agents, asthmatics experience progressive changes in airway structure and cumulative damage to the cells that line the airways (epithelium). The accumulation of damage due to ineffective repair may in part explain the airway’s hyperresponsiveness in asthma and highlights the importance of effective epithelial repair. Ben Patchell seeks to identify molecules that normally contribute to the process of epithelial repair and apply these findings to diseases such as asthma. Specifically, he is studying glycosylation, a process in which certain molecules gain sugars to become fully functional. Glycosylation has previously been shown to be essential in the repair of normal airway cells and there are demonstrated differences between the cells of normal and asthmatic individuals. Ben has developed a method to identify the unknown protein molecules responsible for these differences. Annexin II has been identified as a novel mediator of epithelial repair and has been demonstrated on the surface of airway epithelial cells. Ben is exploring how Annexin II and its associated proteins are regulated and the mechanisms by which they regulate cellular events such as migration in both normal and asthmatic epithelium. He is also investigating the effect of steroids, the primary therapy for asthma, on each of the cellular events. This research could lead to new research strategies and new therapeutics for asthma.
Alterations in hippocampus structure and function during pregnancy and motherhood. The role of corticosterone
Pregnancy and motherhood are life-changing events that often result in cognitive and mood disturbances. Research has shown decreased verbal recall and decreased spatial ability in women during the last trimester of pregnancy. Spatial memory relies in part on the integrity of the hippocampus in the brain, and on the steroid hormone corticosterone, but little is known about the effect of pregnancy and motherhood on these processes and how they relate to memory and learning. Jodi Pawluski is investigating the relationship between corticosterone, hippocampus structure and hippocampus-mediated learning and memory during pregnancy and motherhood. In addition to advancing understanding of how reproductive experience affects neurological, cognitive and hormonal processes in the mother, she hopes her work may contribute to the development of therapies for pregnancy-related diseases such as postpartum depression.
Evaluation of small molecule therapeutics modulating excitotocity in a mouse model of HD
Huntington’s disease (HD) is a progressive neurological disorder characterized by involuntary movements, emotional disturbances and memory loss. There is currently no cure for HD, and the disease is ultimately fatal. HD is caused by a selective loss of a population of nerve cells in specific regions of the brain, particularly the striatum. Accumulating evidence suggests that overactivation of glutamate receptors (transmembrane proteins involved in communication between nerve cells), which are abundant in the striatum, might lead to the selective death of nerve cells observed in HD. Mahmoud Pouladi’s research focuses on evaluating the efficacy of small molecule therapeutics known to target glutamate receptor signalling pathways in a model of HD. His work explores whether restoring physiologic levels of intracellular calcium by modulating glutamate signalling will prevent the neurodegeneration and associated motor and behavioural deficits observed in HD. This study will further our understanding of this disease and provide insights about glutamate signalling as a therapeutic target for the treatment of HD.