Grant Recipients » 2014
The Manitoba Medical Service Foundation has been awarding Research Grants to researchers and students since 1971, and over $19 million has been donated to furthering this cause.
We only keep the last five consecutive years of Grant Recipients online. Contact the Administrative Assistant for information on prior years.
Please Note: Institutional Costs are not eligible expenses for MMSF Grants and Awards funding.
Validation of WWTR1 as a Therapeutic Target in Dedifferentiated Liposarcoma
- Dr. S. Banerji
Important mechanisms contributing to cancer include increased growth of cells, alongside the inability to properly mature into normal healthy cells. Most traditional cancer therapies are directed exclusively at the proliferation of cells and don't alter the cellular maturity. Soft tissue sarcomas (STS) are rare cancers that arise from connective tissue in the body. Most patients are currently treated with high-dose cytotoxic chemotherapy, surgery, and radiation. Despite aggressive treatment, fewer than 20% of patients survive five years from diagnosis. STS accounts for 9% of cancer-specific deaths in young adults in Canada.
Due to these poor patient outcomes and significant toxicity of existing therapies, new treatment approaches are needed. To address this challenge, we have performed extensive genetic and molecular screens in STS tissues and cell lines using new high-throughput technologies to identify candidate targets for the development of new treatment approaches. One of these screens brought to attention the gene WWTRJ as a potential therapeutic target specifically in the dedifferentiated liposarcoma, a subtype of STS that arises from body fat cells. WWTRJ has previously been found to have two major functions: 1) contributes to the proliferation and survival of other cancer cells, and 2) regulates the transformation of normal stem cells to healthy adult body fat cells. The exact function of WWTRJ in dedifferentiated liposarcoma is not yet clear.
For this proposed project, we will do the following: 1) perform the necessary studies to validate WWTRJ as a new target in dedifferentiated liposarcoma by understanding its mechanism of action, 2) determine combinations of drugs that may synergize with WWTRJ, and 3) measure the extent of WWTRJ expression in actual clinical samples. If successful, these experiments would validate a new therapeutic target in dedifferentiated liposarcoma with immediate translational relevance, and help guide the development of future clinic trials. Furthermore, if we can determine that WWTRJ is acting by a mechanism that reverses liposarcoma cell immaturity, this will open an entirely new therapeutic direction in sarcoma that has been sought-after for decades, but until now has remained elusive.
Dr. S. Banerji — Post-Doctoral Fellowship (Cancer Genomics) (Harvard University) 2011; FRCPC (Medical Oncology) (CancerCare Manitoba) 2007; FRCPC (Internal Medicine) (University of Manitoba) 2006; MD (Medicine) (University of Manitoba) 2002; BSc (Medicine) (University of Manitoba) 2000; BSc (with Distinction) (General) (University of Manitoba) 1995
Medical Oncologist, Medical Oncology and Haematology, CancerCare Manitoba
Senior Scientist, Cell Biology, Manitoba Institute of Cell Biology
Assistant Professor, Internal Medicine, University of Manitoba
Preventing Post-Traumatic Stress in ICU Survivors: A Pilot Randomized Controlled Trial of ICU Diaries
- Dr. M. Blouw
Patients who have been in the intensive care unit (ICU) often experience psychological problems, with approximately 20% experiencing symptoms of Post Traumatic Stress Disorder (PTSD). It is thought that PTSD occurs because people do not have a structured memory of the traumatic event.
Researchers in Europe attempted to treat PTSD in ICU survivors through a diary that outlines the patient’s ICU stay, helping them create a whole memory of the traumatic experience. However, this treatment was not compared to other psychological treatments for PTSD. Our pilot study aims to address this gap by testing ICU diaries, and comparing them to an alternate treatment.
We will recruit 40 ICU patients who are predicted to be in the ICU for 72 hours or more, with 24 hours or more on mechanical ventilation. Ten patients will receive the diary intervention, ten an information brochure as the alternate treatment, ten both, and ten nothing. The patients in the ICU diary condition will have a journal at their bedside that family and ICU staff can write in at any time. Staff will be able to take pictures to include in the diary. When patients in the diary and/or information group are discharged, they will be given their documents.
One week after discharge, a research nurse will call patients and ask them about their memories of the hospital using a standardized questionnaire. At 30 and 90 days, patients will receive another call but the questions will be from questionnaires used to measure PTSD, depression, anxiety, general health and social support. We expect that patients who received the ICU diaries and the information brochure will have the lowest PTSD rates 90 days after discharge, followed by those who received the diaries only. We expect those who receive the information brochure only to have lower rates of PTSD than those who received no intervention, but higher rates than those who received the diaries. This study will provide important information about how we can prevent PTSD in this population, thus improving follow-up ICU care and mental health outcomes.
Dr. M. Blouw — Fellow of the RCPSC - Adult Critical Care Medicine (Critical Care Medicine) (University of Manitoba) 2013; Fellow of the RCPSC - Adult Respirology (Respirology) (University of Manitoba) 2011; Fellow of the Royal College of Physicians and Surgeons Canada (RCPSC) - General Internal Medicine (Internal Medicine) (University of Manitoba) 2010; MD (Medicine) (University of Manitoba) 2006; BSc (Science) (University of Manitoba) 2001
Assistant Professor, Internal Medicine/Respirology, University of Manitoba
Assistant Professor, Internal Medicine/ Critical Care, University of Manitoba
Director - Internal Medicine Procedure Service, Internal Medicine/General Internal Medicine, University of Manitoba
Mechanisms of Prostaglandin-E2 Mediated Immunoprivilege of Allogeneic Mesenchymal Stem Cells to Prevent Their Rejection for Cardiac Repair
- Dr. S. Dhingra
Cardiac disease is a leading cause of death in North America. The reduced supply of blood to the heart that occurs in patients with heart disease often leads to myocardial infarction, and decreased oxygen delivery to the heart muscle. Lack of oxygen supply is accompanied by death of contractile cells in the heart. This is a major clinical problem because once injured cardiac cells die, they are not replaced by new ones. Consequently, the loss of heart cells decreases the heart's ability to pump blood, which ultimately manifests as heart failure.
Transplanting stem cells into a damaged heart is a novel treatment of cardiac disease, as stem cells can differentiate to cardiac cells and replace the dead cells. Bone marrow derived allogeneic (unrelated donor) mesenchymal stem cells (MSCs) from young healthy donors have emerged as an ideal candidate cell type for cardiac repair. The initial clinical trials reported that allogeneic MSCs were safe to the patients as no side effects were observed, and transplanted cells improved the heart function. However, late after transplantation MSCs were recognized by the recipient immune system and rejected. Therefore, there is a need for thorough investigation of immune properties of allogeneic MSCs to increase the survival of transplanted stem cells in the heart.
We propose to study the mechanisms of transplanted stem cell rejection in the heart. The present study will also identify the optimal interventions to prevent rejection and enhance survival of transplanted stem cells. This innovative research will provide important information that will help to increase the benefits of stem cell therapy for cardiac repair. The long-term therapeutic objective of this research is directed toward improving the quality of life of patients with heart disease by stem cell mediated cardiac repair and regeneration. The spin-off benefit would be realized by a substantial reduction in costly medications and need for long-term patient care. It can be seen that this research will have a major and positive impact on society and Canada's health care system in particular.
Dr. S. Dhingra — Postdoctoral Fellowship (Regenerative Medicine) (University of Toronto) 2013; Postdoctoral Fellowship (Cardiovascular Physiology) (University of Manitoba) 2009; PhD (Biophysics) (Panjab University) 2006
Assistant Professor, Physiology, University of Manitoba
Investigating the Physiological Function of Uncoupling Protein 2 in Pancreatic Beta Cells and its Contribution to Type 2 Diabetes Development: An In Vivo Approach
- Dr. C. Doucette
Type 2 diabetes (T2D) is a Canadian epidemic affecting aging adults as well as young children, underlining the urgent need to develop new strategies to prevent its onset. Since the discovery of insulin, researchers have been diligently working to understand what regulates its secretion.
Healthy pancreatic beta cells secrete a baseline amount of insulin all day long. When blood glucose levels rise, as they do after a meal, the beta cells secrete a burst of insulin signalling peripheral tissues to take the glucose out of the bloodstream. This is called glucose-stimulated insulin secretion (GSIS) and it is impaired in the diabetic state. Beta cells contain a protein called Uncoupling Protein 2 (UCP2) which interrupts GSIS when expressed. However, it is not known when UCP2 is active on a daily basis or how it contributes to the control of insulin secretion in a natural physiological setting.
When considering that insulin secretion is rhythmic over a 24-hour period and that the maximal capacity for GSIS occurs in the fed-phase of the daily cycle, we have come to hypothesize that UCP2 is active in a rhythmic and predictable fashion. Low UCP2 activity in the fed-state ensures maximal GSIS, whereas up-regulation of UCP2 in the fasted-state prevents insulin secretion. This provides a mechanism to prevent fasting-induced hypoglycemia when blood glucose levels are low. Moreover, we hypothesize that loss of rhythmic cycling of UCP2 contributes to alterations in beta cell function as T2D develops.
To explore these hypotheses, we will develop in vivo studies in a mouse model examining the 24-hour expression patterns of UCP2 and its contribution to daily GSIS rhythms. Moreover, we will determine how the 24-hour expression patterns of UCP2 are altered as T2D develops from the earliest states to overt onset using a well-studied mouse model. It is anticipated that this research will set the groundwork for the development of sophisticated in vivo models that will allow us to mechanistically define methods to restore rhythmic expression of UCP2 in T2D subjects, thus restoring rhythmic insulin secretion and health.
Dr. C. Doucette — PhD (Cell and Systems Biology) (University of Toronto) 2007; BSc (Cell and Molecular Biology) (University of Toronto) 2000
Research Scientist, DREAM Theme, Manitoba Institute of Child Health
Assistant Professor, Physiology, University of Manitoba
The Impact of a Preoperative Exercise Program on Fitness Outcomes Following Bariatric Surgery
- Dr. K. Hardy
Canada has one of the highest obesity rates in westernized countries. Obesity has many health related complications, including high blood pressure, high cholestorol, diabetes, sleep apnea and osteoarthritis. Bariatric (weight loss) surgery is the most effective way of achieving long-term weight loss and treating the complications of obesity. While the period leading up to surgery is considered an important opportunity for lifestyle modification, evidence to support recommendations for a supervised preoperative exercise intervention is lacking.
The objective of this study is to measure the short and intermediate-term benefits of a preoperative exercise intervention on patients awaiting publicly-funded bariatric surgery in Manitoba. The primary outcome will be improvement in general exercise capacity as measured by change in a 6-minute walk test (how far a person can walk on a flat surface in 6 minutes). Other outcomes will include excess weight loss, change in body composition, and strength testing.
It is hypothesized that a preoperative exercise intervention will result in improved exercise capacity and general fitness in the short and intermediate-term post-bariatric surgery. Patients who are awaiting publicly-funded bariatric surgery in Manitoba will be offered the opportunity to participate in a randomized study between usual preoperative care and usual care plus a supervised exercise program. Usual care will involve multidisciplinary evaluation and preoperative counseling with a kinesiologist. In the intervention group, patients will participate in a 12-week supervised exercise program at the Reh-fit Centre.
Currently there are approximately 200 patients undergoing publicly-funded bariatric surgery annually in Manitoba. If this study demonstrates a benefit to preoperative exercise, the results will be used to support an application to Manitoba Health for routine implementation of a similar intervention for all patients awaiting publicly publicly-funded surgery in Manitoba. It will also be used to support an application for a larger multi-institutional study of preoperative exercise at several Canadian bariatric centres.
Dr. K. Hardy — Fellowship in Minimally Invasive Surgery (General Surgery) (University of Toronto) 2010; FRCSC (General Surgery) (University of Manitoba) 2008; MD (Medicine) (University of Toronto) 2002; BSc (Biology) (Brandon University) 1998
Assistant Professor, Surgery, University of Manitoba
Staff Surgeon, St. Boniface Hospital
Staff Surgeon, Victoria General Hospital
Manitoba Intra-Operative MRI for the Study of Acute Stroke (MIMRIAS)
- Dr. A. Kanungo
Stroke is a leading cause of death and disability in Canada. About 80% of strokes are caused by blood clots interrupting blood flow to the brain. Reopening the artery to restore blood flow is the cornerstone of treatment. Clot busters given intravenously can prevent great disability, but this therapy is limited to less than 5% of stroke sufferers.
Patients presenting to emergency greater than 4.5 hours after the onset of symptoms or with potential bleeding complications are ineligible for treatment due to the risk of catastrophic brain hemorrhage. Recent advances in endovascular technology hold promise for treating a wider number of people as this technology directly targets the occluded artery to re-establish blood flow to the brain. Theoretically this should reduce hemorrhagic complications, and extend the therapeutic window. However, neurological outcomes after such treatment have shown mixed results.
To advance the treatment of acute stroke, we must develop and validate new diagnostic technologies to help identify who would benefit from endovascular therapy. Computed Tomography (CT) is currently used to diagnose acute stroke, but it is of limited utility in selecting patients for endovascular treatment as CT images taken during the early stages of stroke are often normal or show only subtle changes. By comparison, magnetic resonance imaging (MRI) can reveal the extent of brain tissue at risk within minutes of stroke onset without exposing the patient to harmful radiation. Multiple scans can be taken to observe the changes to brain tissue in real-time. This helps us better understand how stroke evolves during the first 24 hours after endovascular rescue, which is invaluable for developing strategies to mitigate the treatment risks, and identify potential options for therapeutic intervention.
This will allow us to test the hypothesis that MR brain imaging can identify patients that are expected to improve clinically after successful endovascular treatment. Thus, this study will be the first but essential step in the development of new clinical guidelines aiming to improve the safety of endovascular approaches to acute stroke.
Dr. A. Kanungo — MD (Medicine) (University of Calgary) 2012; PhD (Molecular Biology) (University of Toronto) 2007
Neurology Resident, Neurology, Winnipeg Regional Health Authority
Molecular Characterization of Multidrug Resistance in Pseudomonas Aeruginosa
- Dr. A. Kumar
Widespread antibiotic resistance of bacterial pathogens is leading to concerns that the era of untreatable infections is not too far in the future. With our arsenal of antibiotics depleting fast and the search for new antibiotics becoming increasingly scarce, novel approaches to treat resistant infections are urgently needed.
Pseudomonas aeruginosa, a Gram-negative pathogen, is one of the leading causes of hospital-acquired infections in Canada. These infections are very challenging to treat because of the organism's resistance to almost every antibiotic in clinical use. The most important mechanism of intrinsic antibiotic resistance in Pseudomonas aeruginosa is through the activity of proteins called efflux pumps, particularly those belonging to the Resistance-Nodulation-Division (RND) family of proteins. These pumps form a tripartite structure which captures the antibiotic molecule from inside the cell and pumps it out in an energy-dependent fashion so the antibiotic concentration inside it never reaches the critical level which can cause the cell's death.
Another astonishing feature of these pumps is that one pump can efflux out a variety of different antibiotic molecules with very different chemical properties. They are therefore considered the major contributing factor to the phenomenon of multi-drug resistance, where a bacterial cell is resistant to more than three different classes of antibiotics. Consequently, most of the antibiotics against P. aeruginosa are rendered useless because of the activity of these pumps.
It is believed that if we were able to inhibit the activity of RND pumps, we would be able to reuse a number of antibiotics against Pseudomonas aeruginosa that are currently ineffective due to their activity. In this application, we propose to study the molecular mechanisms involved in the formation of the tripartite structure of these pumps. The knowledge gained from this work can lead to novel ways of inhibiting their activity by disrupting the formation of this complex, which is required for the pump activity. This knowledge can further be applied to pumps in other bacterial pathogens, and aid in designing innovative therapeutic options for the treatment of antibiotic resistant infections.
Dr. A. Kumar — PhD (Microbiology) (University of Manitoba) 2005; MSc (Microbiology) (Dr. RML Awadh University, India) 1999; BSc (Microbiology, Chemistry) (Dr. RML Awadh University, India) 1997
Assistant Professor, Microbiology, University of Manitoba
Targeting Lysine-Specific Demethylase for the Treatment of Breast Cancer
- Dr. T. Lakowski
DNA is the language of life written in 20,000 "blueprints" called genes. The amount of a gene that is made is as important as the gene’s DNA sequence, and can alone cause disease. An example is breast cancer, which is caused by the overproduction of certain genes.
A series of inherited, small chemical modifications to the proteins associated with DNA help to dictate gene production. The study of these modifications is known as epigenetics. The types and positions of chemical modifications to proteins constitute an epigenetic code controlling production of the neighboring gene. Some types of breast cancer result from misprinting of the epigenetic code causing inappropriate changes in the production of specific genes. Therefore drugs targeting the epigenetic process may be treatments for breast cancer.
My goal is to develop drugs that interfere with one of the established epigenetic processes involved in breast cancer. As part of this proposal, we will develop methods to directly observe epigenetic processes that are involved in breast cancer. We will produce a protein involved in this epigenetic process. We will then develop methods to directly observe the activity of this protein. Finally, we will develop candidate drugs that bind to and inhibit the activity of the protein. The goal will be to rewrite the epigenetic code in order to stop breast cancer. The candidate drugs may eventually be developed into novel treatments for breast cancer.
Dr. T. Lakowski — PhD (Pharmaceutical Sciences) (University of British Columbia) 2006; BSc (Pharmacy) (University of British Columbia) 1999
Assistant Professor, Pharmacy, University of Manitoba
Biological Prognostic Markers in Diffuse Large B-cell Lymphoma: A Population Based Study
- Dr. A. Perry
Non-Hodgkin lymphoma (NHL) is a cancer of white blood cells that normally live in lymph glands. The most common type is diffuse large B-cell lymphoma (DLBCL). Over a hundred people are diagnosed with DLBCL every year in Manitoba. With current chemotherapy, six of every ten new patients can be cured. However, the remaining patients have a poor response to chemotherapy, and many will die.
Currently, we are not very good at predicting who will do poorly. Standard practice is to take into consideration patient age, overall health, and extent of lymphoma in the body (biological factors), but we know that DLBCL often looks different under the microscope or when assessed by pathologists. This project's goal is to understand more about biological factors in DLBCL so that this information can be used in assessing patients. This could improve our ability to predict whether a patient will be cured. Patients whose DLBCL has "bad" biological factors may need more aggressive treatment.
The study will be performed on 300 patients diagnosed with DLBCL in Manitoba between 2005 to 2012. The variables will include age, gender, laboratory data, and stage of disease. Pathologists will study the lymphoma tissue obtained at diagnosis by doing specialized stains and evaluating if the stains are positive or negative. Analysis called ''telomere length measurement" will be done to determine how susceptible an individual's genetic material is to damage and whether knowing the length tells us anything about their lymphoma. The information collected will be analyzed using statistical methods to see what biological factors best predict relapse and survival.
This study would be the first to investigate a large number of clinical and biological factors in a group of DLBCL patients receiving current treatment. It could lead to use of biological factors routinely at the time of diagnosis in future patients. Patients appreciate knowing as much as they can about their prognosis. Additionally, this research could improve the outcome of DLBCL patients by furthering the ability to identify high-risk patients likely to fail standard chemotherapy, but who may benefit from alternative approaches.
Dr. A. Perry — MD (Medicine) (University of Zagreb School of Medicine) 2004
Hematopathologist, Division of Hematopathology, Diagnostic Services of Manitoba
Assistant Professor, Pathology, University of Manitoba
The Relationship Between Concussion and Academic Performance Among Manitoba Students in Grades 9 to 12
- Dr. K. Russell
Concussions, or mild traumatic brain injuries, are common injuries in youth. Between 2005 and 2010, approximately 23,000 Manitobans were diagnosed with a concussion with 30% occurring among 14 to 18 year olds. Physical and mental rest are cornerstone in the treatment of concussions and youth often take longer to recover than adults because their brain is still developing. Cognitive rest refers to resting the brain by limiting reading, television, video games, computer use, texting, or performing activities that require mental concentration. The school environment does not encourage cognitive rest and symptoms can get worse in students who return to the classroom before they are free of symptoms.
The objective of our study is to examine the effects of a concussion during the academic year on students' end of year, teacher-assigned grades compared with those from the previous year. We will include all Manitoba students in grades 9 to 12 who had a concussion diagnosed by a doctor between 2005 and 2011. For each student with a concussion, five who were enrolled at the same schools but not diagnosed with a concussion will be randomly included. This will allow us to control for any changes in teacher- assigned grades that may naturally occur as students' progress through high school.
A grade point average will be calculated from their percentage grades in math, sciences, language arts, social studies, and foreign languages. A change will be calculated by subtracting the pre-concussion average from the post-concussion average. If the change in grade point average is negative, the student's average will be lower after their concussion. Grades will also be studied to see if they change from the year before to the year after the concussion.
This evidence will help inform parents, teachers, school administrators, and physicians on what to expect when students return to the classroom. It will also help guide the development of Return-to-Learn guidelines that will explain how to best reintegrate students back into the classroom and create a learning environment to support students who have recently had a concussion injury.
Dr. K. Russell — Postdoctoral Fellowship (Traumatic Brain Injury) (St. Michael's Hospital) 2012; PhD (Epidemiology) (University of Calgary) 2011; MSc (Epidemiology) (University of Alberta) 2006; BSc (Biological Sciences) (University of Alberta) 2000
Assistant Professor, Pediatrics and Child Health, University of Manitoba
Research Scientist, Manitoba Institute of Child Health
Assessment of Cardiac Involvement by Cardiac Magnetic Resonance in Adolescents With Severe Anorexia Nervosa
- Dr. D. Schantz
Anorexia nervosa (AN) is an eating disorder in which an individual restricts food intake to the point of starvation. It is infrequently diagnosed in adolescents. It is well known that subjects with AN may develop medical complications involving multiple systems including the heart. Because of this, patients are often tested with electrocardiograms (which assess the hearts electrical activity) and echocardiograms (that tests the structure, size, and function of the heart).
Cardiac MRI (CMR) is another tool for evaluating the structure and function of the heart. CMR allows for much more complete imaging and overcomes some of the limitations of echocardiography. CMR also provides a more accurate assessment of heart function, and is able to visualize scarring in the heart muscle which may be the result of an injury to the heart. This is a study in which we will evaluate adolescents with AN using CMR. We think it will be better at identifying heart abnormalities, and will allow us to assess for scarring of the heart muscle. We will also see if any abnormalities are related to the severity of their AN.
Adolescents (12 to 18 years) with eating disorders in Manitoba are followed by the Winnipeg Health Sciences Centre Child and Adolescent Eating Disorder Service. Patients who have a weight of less than 80% of their expected body weight will be invited to join the study. The patients will have an electrocardiogram and echocardiogram at the Variety Children's Heart Centre on one day. On another day, they will go to the MRI department of the St. Boniface hospital where they will undergo a CMR study. Once the CMR is complete, their participation in the study will be complete.
We expect to find a higher number of cardiac abnormalities in anorexia nervosa patients using CMR compared to using echocardiography because CMR gives us better measurements of the heart. We hope that this will guide us in how we manage patients with AN. The findings of abnormalities based on CMR may also provide motivation for those struggling with this illness.
Dr. D. Schantz — MD (Medicine) (University of Manitoba) 2004; BSc (Biology) (University of Manitoba) 2000
Assistant Professor, Pediatrics, University of Manitoba
Assessment of Oral Health in Youth With Type 2 Diabetes Mellitus
- Dr. S. Todescan
This project intends to evaluate the oral health in youth with type 2 diabetes (T2DM) and determine if those with T2DM and high sugar levels have more decay, gum disease and bone loss around teeth than patients with sugar levels under control. The youth with T2DM will be recruited from Diabetes Education Resource for Children and Adolescents (DER-CA). They will have an examination of their teeth and gums by a dentist during their regular visits at DER-CA and be invited to participate in the study.
Following the exam, the patient will receive instructions and tools to help clean their teeth. Some diabetes-related information will be collected from the DER-CA chart, including duration of diabetes (years since diagnosis); current medications; current laboratory data (glycated hemoglobin [HbA1c]; lipid profile); Body Mass Index Z-score (BMI-z); blood pressure; and waist circumference. By doing this, the investigators aim to look for an association between oral health and T2DM. All youth with T2DM will be included in the study.
It is anticipated that youth with T2DM will present high prevalence of gum disease, bone loss around teeth, and decay. It is also expected that youth with high sugar levels may present even higher prevalence of gum disease, bone loss around teeth, and decay in comparison to youth with sugar under control. There is no information in the dental literature involving oral health assessment of a population of youth with T2DM. The youth may have a potential risk of developing more severe gingivitis, periodontitis, and tooth decay very early in life.
The research will help to better understand the impact of diabetes to oral health, and to design programs to address oral health needs in youth with diabetes. Manitoba has some distinct advantages for conducting this study because of the high occurrence of T2DM in youth, well-established partnerships with Aboriginal groups and communities, and there being only one diabetes centre for youth in the province.
Dr. S. Todescan — FRCDC (Fellow Royal College of Dentist of Canada) (Periodontics) 2012; Postdoctoral Fellowship (Oral Biology) (University of Toronto) 2004; PhD (Periodontics) (University of Sao Paulo, Brazil) 1999; MSc (Periodontics) (University of Sao Paulo, Brazil) 1996
Assistant Professor, Dental Diagnostic and Surgical Sciences, Periodontics, University of Manitoba
Examining the Role of the Antioxidant N-Acetylcysteine in Hypoxia as a Model System for the Development of Hypoxia-Activated Prodrugs
- Dr. G. Tranmer
Hypoxia in cancer is defined as a lack of oxygen in solid tumors due to a reduction in blood supply to the surrounding tissue. Unfortunately, when a tumor becomes hypoxic, the cancer can become resistant to chemotherapy and the tumor can turn into an aggressive form of cancer. As a result, it is important for doctors to understand when a tumor becomes hypoxic, as well as the role of hypoxia in cancer, in order to treat patients properly.
This project is designed to develop the tools to study hypoxia, and to develop molecules known as hypoxia-activated prodrugs (HAP) that specifically target hypoxia in cancer cells. A HAP is attached to a cancer drug or imaging agent, and under oxygen-poor conditions releases the agent into the tumor while remaining intact in normal tissue. HAPs are designed to be triggered only in tumor hypoxic zones, specifically targeting hypoxic tumor cells and leaving normal cells unaffected.
The main objective of this proposal is to create a model system that will aid in the development of new HAPs using N-acetylcysteine as a tool to measure a compound’s ability to act as a prodrug. Specifically, I plan to investigate the behaviour of the antioxidant N-acetylcysteine (NAC) and its derivatives under hypoxic conditions, using reactive oxygen species and apoptosis (cell death) as a measuring point. The level of reactive oxygen species generation, and resultant apoptosis, will serve as an indicator of the ability of our newly developed hypoxia-activated functional groups to act as prodrugs, with efficient prodrugs lowering reactive oxygen species levels through the release of N-acetylcysteine and subsequent antioxidant behavior.
The long-term purpose of this project is to understand the factors affecting a compound’s ability to act as a HAP, and to develop general rules for the classes of compounds that make efficient HAPs. Furthermore, the project will evolve into the synthesis of new HAPs that will be used for targeted cancer therapies of hypoxic tumor regions, and for selective imaging of hypoxic tumors.
Dr. G. Tranmer — PhD (Organic Chemistry) (University of Guelph) 2003; BSc (Hon.) (Chemistry) (Brock University) 1998
Assistant Professor, Pharmacy, University of Manitoba
Measuring Polyethylene Wear in Total Knee Replacements Using Radiostereometric Analysis: A Retrospective Analysis of Short-Term Radiographs
- Dr. T. Turgeon
Knee replacement surgery is a common procedure in Canada with over 50,000 knees being replaced each year. Knee replacements typically consist of three main parts: a curved metal piece fitted to the lower end of the thigh bone, a flat metal piece fitted to the top end of the shin bone, and a small plastic (polyethylene) insert that acts like cartilage to reduce friction between the two metal parts.
Because the plastic is a softer material than the metal, it slowly wears away. Modern plastic inserts will typically last for at least 15 to 20 years. Currently, regular x-rays used by most surgeons to monitor patient's implants cannot detect wear of the implants until it is very obvious and possibly painful. Radiostereometric analysis (RSA), however, is a type of x-ray that can give a precise picture of a person's knee replacement. It has the potential ability to measure the wear of the plastic insert much earlier than regular x-rays and can inform the surgeon of how quickly the insert is wearing before it becomes painful.
This research study will determine the rate of insert wear between implantation of the artificial joint to the patient's two year follow-up appointment. This study will utilize RSA x-rays which were obtained from 102 patients who received the same type of total knee replacement. These x-rays will be re-analyzed to determine the joint space for each patient at each follow-up period. The measured joint space will be used to determine the amount of plastic wear for each RSA x-ray.
It is hoped that the results of this study will allow surgeons and researchers to closely monitor the wear performance of a patient's knee replacement to catch problems early and avoid painful revision surgery. By demonstrating the ability of RSA to measure polyethylene wear after a short interval of time, we can provide joint replacement manufacturers and health care providers with an effective tool for evaluating new, untested knee replacement products on a small number of patients before they are used in hundreds or thousands of patients.
Dr. T. Turgeon — Masters of Public Health (Epidemiology) (San Diego State University) 2004; MD (Medicine) (University of Western Ontario) 1998; BSc (Chemistry) (University of Western Ontario) 1995
Assistant Professor, Surgery / Orthopaedics, University of Manitoba
Mechanical Modulation of Transforming Growth Factor Beta Responses in Airway Smooth Muscle Cells
- Dr. A. West
Of all respiratory diseases, asthma affects the most people with approximately three million Canadians and over 300 million people worldwide suffering from it. The narrowing of the airway that leads to breathing difficulties in asthma comes largely from the airway smooth muscle (ASM), which surrounds the airway, contracting too frequently and easily. Many researchers believe that changes in ASM contraction are from ‘signaling chemicals’ that immune cells in the airway use to communicate with each other. However, asthma also causes significant structural changes in the lungs, including a thickening and stiffening of the airway wall, which can significantly change how the cells function.
Since most researchers use cells grown on flat two-dimensional (2D) plastic surfaces, which are much stiffer than real airways, it is difficult to understand how the signaling chemicals might cause disease. I believe that the structural changes seen in the lungs of asthmatics help to ‘turn on’ the signaling pathways that cause the abnormal ASM contraction in asthma. In this project, I will change the structural environment for ASM cells to see how different combinations of signaling chemicals and structural changes might cause changes in ASM function in asthma.
I will make hydrogels that are similar to traditional 2D plastic surfaces for growing cells, but that are more like the stiffness of the airway wall. Then a process known as tissue engineering will be used to create miniature strips of ASM from isolated ASM cells. These three-dimensional (3D) ‘microtissues’ offer a superior method to study ASM because the 3D environment is known to be important for many cellular processes.
I will make hydrogels and microtissues that directly imitate the structural changes seen in tissues in asthmatics, and compare them with soft hydrogels and microtissues by measuring ASM contraction and other important features of ASM function. Seeing what causes cells in stiff and soft environments to behave differently in response to signaling chemicals will give us a much greater understanding of how ASM changes in disease, and may help us find new treatments to improve the health of asthma patients.
Dr. A. West — PhD (Physiology) (University of Western Australia) 2007; BSc (Hon.) (Physiology) (University of Western Australia) 2001
Assistant Professor, Physiology, University of Manitoba
Research Scientist, Biology of Breathing, Manitoba Institute of Child Health
Yin Yang Gene Expression Ratio Signature for Breast Cancer Prognosis
- Dr. W. Xu
A group of genes whose expression status can distinguish high risk from low risk patients is called a prognostic signature. Several gene prognostic signatures have been identified and are used in clinics. However, there is little agreement between numerous prognostic signatures when generated from different studies.
We hypothesize that there are two opposing effects in cancer cells, Yin and Yang, whose balance determines the fate of the cancer cells and outcome of the patient. Genes expressed higher in normal breast tissues than in breast cancer cells are called "Yang" gene candidates and the reverse are called "Yin". Our theory provides a simple way to calculate the patient risk scores - the Yin and Yang gene expression Mean Ratio (YMR) - since it represents the balance of the Yin and Yang effects within the cancer cells.
We will test the YMR signature among patients who did not receive treatment. The patients who have high YMR will be considered high risk. Using patients' clinical data, we will validate whether the high risk patients predicted by YMR actually had shorter survival time, and whether low risk patients had longer survival time. If the YMR is low in patients who receive a specific therapy, the YMR indicates a predictive signature for this effective treatment. We will also compare YMR signature with previously reported breast cancer prognostic signatures.
The validation results using public data can be used in clinic patients. A patient who has high YMR will be recommended for intensive treatment; low risk patients would be spared unnecessary or over treatment. This study will further prove the innovative Yin Yang balance concept and provide a novel insight into the biology of breast cancer development. In particular, we will deliver a gene list panel for YMR signature detection which will help the clinic setting for breast cancer patients. Finally, this study can also have potential for drug development by modulating the Yin and Yang or altering other target gene expression so that a lower YMR can be achieved.
Dr. W. Xu — BSc (Computer Science) (University of Manitoba) 2001; PhD (Microbiology and Immunology) (Nanjing Agricultural University and Shanghai Institute of Biochemistry, Chinese Academy of Sciences) 1992
Adjunct Professor, Pharmacy, University of Manitoba
Bioinformatician, Manitoba Institute of Cell Biology
Bioinformatician, Manitoba Institute of Child Health
Neonatal Chronic Lung Disease in a Double-Hit Rat Model Induced by Postnatal Hyperoxia and Intermittent Hypoxia: Closer to Clinical Features?
- Dr. M. Yi
The average incidence of preterm delivery across the world has increased from 8-9% in the 1990s to about 10-13% today. Preterm delivery is the birth of a baby that is less than 37 weeks gestational age. Supplemental oxygen is one of the most common treatments in the care of preterm infants. The evidence base for deciding which newborns need it, and what the appropriate dose remains weak.
Oxygen therapy was first introduced in the 1940s and by the 1950s; approximately 10,000 preterm children had been blinded as a result of it. Randomized trials confirmed that liberal oxygen therapy might cause retinopathy of prematurity and contribute to the development of chronic neonatal lung injury.
In the 1960s, oxygen therapy was restricted and many nurseries adopted arbitrary upper limits for the concentration of inspired oxygen. More recently, five randomized trials were initiated to examine the efficacy and safety of decreasing the concentration of supplemental oxygen. The results showed that babies who were restricted to low oxygen had higher death rates. We hypothesize that frequently fluctuating premature infants between limited oxygen and increased oxygen might lead to their death. We will use newborn rat pups to test our novel idea. Should this research be informative, it would alter our current clinical practice.
Dr. M. Yi — Neonatal Parental Fellowship (Neonatology) (SickKids Hospital, University of Toronto) 2009; Research Fellowship (Lung Biology) (SickKids Hospital, University of Toronto) 2007; PhD (Physiology) (China Medical University) 2000; MD (Pediatrics) (China Medical University) 1995
Assistant Professor, Pediatrics/Neonatology, University of Manitoba
Adjunct Professor, Physiology, University of Manitoba
Assistant Professor, Biomedical Engineering, University of Manitoba
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