Spinal cord injury mostly occurs in young people, causing debilitating, lifelong disability. Stroke mostly occurs in older people, and is a leading cause of disability in the elderly. In both cases, recovering function relies on the ability of the central nervous system (CNS) to rewire itself. But the CNS isnât very supportive of the integral processes required for rewiring to occur. Rewiring requires nerve cells to sprout new fibres (called axons) and subsequently make new connections in the spinal cord by bypassing the damaged area. Rewiring also relies on the birth of new cells that must migrate to the injury site and replace cells that died as a result of the injury. Finally, new blood vessels must also grow back into the damaged area to sustain the regeneration of the new tissue. Each of these processes is controlled by the âextracellular matrix,â the environment surrounding cells. Dr. Adele Vincent is examining how this matrix can be manipulated to improve repair processes in the central nervous system. She is investigating whether SPARC, a protein that regulates interactions between cells and the extracellular matrix, can be used to promote recovery after stroke. Dr. Vincent is studying the role of SPARC in regulating processes that impact on nerve regeneration after injury, such as neural stem cells, new blood vessel formation, and the inflammatory response. Ultimately, these findings could lead to more effective therapies to stimulate regeneration following traumatic injuries, stroke and neurodegenerative diseases.
Program: Trainee
Mechanical stress: an unexplored factor in regulation of cell signaling in DCIS and early breast cancer progression
Breast cancer is the second most common cause of cancer-related deaths among women in Canada. Deaths caused by invasive breast cancer that metastasizes (spreads to other parts of the body) are mostly preceded by a pre-invasive stage of the disease called ductal carcinoma in-situ (DCIS). This early stage is the ideal target in prevention of invasive breast cancer. Research has confirmed that features of the molecular activity of normal wound healing may play an important role in the spread of cancer from one area of the body to another. As cancer develops within any organ there is disruption of normal tissue. This disruption is like a wound and the response is like a scar. This process results in new mechanical forces within the tissue that act like a stress on tumor cells and have the potential to strongly influence a large number of cellular processes associated with tumor growth and invasion. Dr. Jiaxu Wang is researching the role of mechanical stress on cancer cells. He is investigating which genes are altered by mechanical stress in breast cancer cells. Wang is also identifying genes that are specifically altered by mechanical stress but not by other forms of stress that are known to exist in cancer tissues, such as lack of oxygen, to determine if these genes can be used to measure mechanical stress in DCIS lesions. The research will contribute to a better understanding of the specific role of mechanical stress in breast cancer progression. Wangâs ultimate goal is to develop markers that can predict or provide targets for therapy to improve outcomes for women with pre-invasive and early breast cancer.
Effects of Prenatal Psychotropic Medication Exposure on Critical Periods of Language Development
Psychotropic medications like benzodiazepines (tranquilizers used to control anxiety) and serotonin reuptake inhibitors (antidepressants used to treat depression) are frequently prescribed during pregnancy to manage depression and anxiety, even though these drugs have not been approved for this purpose, and the impact on infant development is unclear. These drugs increase the activity of certain chemicals in the brain that inhibit nerve cell activity. Whitney Weikum is expanding on her earlier MSFHR-funded research on language development in infants. Now Weikum is studying the effects of prenatal exposure to psychotropic drugs on critical periods of infant language development. During the first years of life, infants rapidly and almost effortlessly acquire language. There appear to be a number of discrete periods critical for acquiring language information. At birth, infants have the ability to discriminate almost all the distinctive sounds from the worldâs languages. Weikum is testing infantsâ responses to different language sounds at 36 weeks gestation, as newborns, and during the first year to learn whether psychotropic drugs affect cognitive and language development. The results will be compared to women who experienced depression, but did not take medication, to determine the impact of depression alone on infantsâ language development. The goal is to help women and physicians make informed decisions about whether to use psychotropic medications during pregnancy.
Characterization of the assembly of type III secretion system of pathogenic Escherichia coli
The type 3 secretion system (T3SS) is a multi-protein complex that plays a central role in the virulence of many bacteria categorized as Gram-negative. Gram-negative bacteria include some of the most harmful bacteria to humans and plants. T3SS directs the secretion and transfer of bacterial proteins into the cytoplasm â the portion of the cell outside the nucleus of eukaryotic cells. Itâs known that the secretion system is composed of about 20 to 25 different proteins arranged into two distinct parts called the needle complex and the translocon. However, the exact mechanisms of how proteins are secreted by T3SS and the precise molecular organization of the complex are poorly understood. Dr. Neta Wexler Sal-Man aims to define, at the molecular level, the interactions of proteins that create the secretion apparatus of two pathogenic bacteria: Enteropathogenic E. coli and enterohemorrhagic E. coli. In the long term, she hopes to identify a way to manipulate the secretion system in order to inject desired proteins or molecules into eukaryotic cells. The research will help improve understanding of this highly complex type 3 secretion system and could ultimately contribute to the design of new therapeutic drugs aimed at the potentially deadly bacteria that use T3SS.
Defining the role of FOXP3 in human CD4+ T cells
In recent years, new immunosuppressive drugs have made considerable improvements to the success of transplantation procedure and the treatment of autoimmune diseases. Despite these successes, the side effects of long-term drug treatment invariably decrease patientsâ quality of life and cause generalized suppression of the immune system. To develop a more direct approach for these therapies, efforts are now focused on a particular aspect of the immune system that controls the response. T regulatory (Tr) cells are a subset of white blood cells that have the ability to suppress undesired immune responses, while leaving other aspects of the normal immune system intact. A gene named FoxP3 has been identified as the master controller for development of a subset of Tr cells that can provide protection against some types of autoimmune diseases and promote acceptance of foreign tissue in a transplant setting. FoxP3 plays an essential role in maintaining normal immune function, but the exact mechanisms by which this gene operates in Tr cells are not known. Due to the high potential for using Tr cells for immunomodulatory therapies, Sarah Allan is investigating the role of FoxP3 in human cells. Her research will increase our understanding of how Tr cells arise naturally, the mechanisms by which they suppress immune responses and how they differ from other types of T cells at the molecular and genetic level. This work will contribute to the development of novel therapies for autoimmune diseases, transplantation, and other pathologies of the immune system.
The structure and process level determinants of improved clinical outcomes in prehospital cardiac arrest and major trauma
Emergency Medical Services (EMS) systems provide care to complex patients under less than ideal circumstances. Paramedics treat patients without knowing much about the patientâs medical history or the cause of the emergency. This makes it very difficult to know how to evaluate the care provided to them. Generally, quality of care in medicine is evaluated by measuring the effect of various components of the system and the interaction between the clinician and the patient, to see the effect on the patientâs health. EMS managers evaluate factors such as the number of ambulances per population, the level of training of paramedics and 911 call response times. Recent research has called into question the theoretical relationship between improved quality of care and the level of training for paramedics, leaving EMS system managers with the difficult task of re-evaluating their assumptions about how to improve the quality of their systems. Douglas Andrusiekâs research will help managers by exploring the relationships between each component of the Emergency Medical System. He will conduct a statistical analysis to determine which structural and care components contribute to better patient care. While most research evaluates only cardiac arrest performance, this project is also examining EMS care of major trauma patients. Andrusiekâs research will lead to the development of strategies that will improve patient care for all British Columbians who suffer acute injury and illness.
Mechanisms for selectivity of vascular-disrupting anti-cancer therapies
Solid cancers rely on blood vessels for delivering the oxygen and nutrients that allow them to grow and metastasize (spread to other parts of the body). Chemotherapy treatment also relies on the vessels for effectively delivering anti-cancer drugs to the tumour cells. When blood vessels have abnormal features, such as in cancerous tumours, the tumours appear to be more resistant to conventional chemotherapies as the result of this abnormal vasculature. A new focus in cancer research attempts to exploit vessel abnormalities that are specific to cancer by using them as cancer therapy targets. A new class of anti-cancer drugs currently under development and in clinical trials targets the blood vessels that supply tumours in two ways: vascular targeting agents (VTAs) damage the existing blood vessels that supply tumours, while anti-angiogenic agents (AAAs) inhibit the growth of new vessels. Although VTAs cause catastrophic damage to blood vessels in the centre of tumours, they leave a rim of viable cells and vessels at the periphery that survive to regrow the tumour; AAAs are also only effective on select populations of vessels within a tumour. Jennifer Baker is studying whether vascular targeting and angiogenic agents will work more effectively in combination with eachother or with other conventional chemotherapies to stifle this subsequent tumour growth. Baker is examining which blood vessels are sensitive or resistant to the drugs, what damage the drugs cause, and how this damage affects tumour growth. The findings could result in more effective combined treatments that are capable of cutting off the blood supply to cancerous tumours, thereby preventing the tumour from growing and metastasizing.
Molecular Epidemiology of Gastric and Esophageal Cancer Survival
Cancers of stomach and esophagus (the tube from the mouth to the stomach) are a major cause of illness and death. Worldwide, the incidence of tumours at the stomach-esophagus border is increasing more rapidly than any other type of cancer. Historically, gastric and esophageal cancers have been studied separately; however, recent evidence suggests these cancers have a lot in common. As a result, studying these cancers together may result in information about the origin or effective treatment of one cancer having similar implications for the other. Morteza Bashash is investigating whether certain genes are associated with the disease progression of these cancers. Specifically, he is testing whether these patients have alteration of two groups of genes that are associated with cancer progression, Matrix Metalloproteinase (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP). He is monitoring newly-diagnosed patients to determine whether the progression of the disease depends on these genes or other possible determinants such as family history, and/or the patientsâ ethnicity. He is also assessing whether the effects are different in geographic areas where the cancers are becoming more common (BC), and areas where the cancers are already common. The results from this research could help identify high risk patients and provide them with more effective treatment.
Identification of Predictive Drug Response Signatures and Novel Resistance Genes by Whole Genome Profiling of Lung Tumors
Lung cancer causes more than a quarter of cancer deaths in Canada, with five-year survival rates among the lowest for commonly diagnosed cancers. Non-small cell lung cancer accounts for about 80 per cent of all lung tumours. Unfortunately, many cases are inoperable by the time theyâre diagnosed, leaving chemotherapy as the main option for treatment. However, response to chemotherapy varies, and the presence of even a small number of unresponsive tumour cells can cause the disease to recur. With his second MSFHR award, Timon Buys is continuing his research on identifying genetic alterations in lung cancer tumours. He is working to identify genomic âsignaturesâ that might predict how effective a drug will be in treating a given tumour. Using âarray comparative genomic hybridizationâ â a technology that allows researchers to assess cancer-associated gene alterations throughout the whole human genome â Buys will characterize the genetic changes in lung tumour tissue that has been isolated from patients before and after treatment. He will use this data to determine whether mis-regulation of specific genes is associated with a patientâs response to different types of chemotherapy treatments, essentially identifying those genes that play a role in resisting drug activity. As resistance genes are identified, treatment strategies can be tailored so that they will be most effective for a specific tumor. This approach to âpersonalized medicineâ â matching treatments to the genetic make-up of individual tumors â may greatly improve patient survival rates.
Modulating proteolysis in Huntington disease: Eluding the toxic fragment
Huntingtonâs disease is an inherited neurodegenerative disorder primarily caused by the early death of brain cells. The disease typically begins with mental and emotional disturbances, which progress to involuntary, jerky movements. An abnormal form of the Huntingtin protein is associated with Huntington’s disease. Huntingtin is made of 3144 amino acids, or molecular building blocks. In a landmark study, after mutating just one of those building blocks, genetically modified caspase-resistant mice (those resistant to intracellular proteins that lead to cell disintegration) were completely protected from all symptoms of Huntingtonâs disease. Jeffrey Carrollâs research aims to find medical interventions beyond genetic modification that produce the same effect. He is developing tools to quickly analyze the effectiveness of drugs at inhibiting cell disintegration. He has designed and is building a cell-based system that allows him to screen libraries of hundreds of thousands of drugs that might offer some protection. Carroll is also investigating a protein-cutting enzyme, caspase-2, whoâs activity is dramatically reduced in caspase-resistant mice. Carroll aims to increase understanding of the pathway between Huntingtin and caspase-2. Findings could contribute to therapies for Huntingtonâs disease.