A protease is an enzyme that can split a protein into peptides. Alterations in normal protease expression are known to be involved in the development of cancer, arthritis and various lung, neurological and cardiovascular diseases. As a result, many proteases and their substrates are an important focus of attention as potential drug targets. Among proteases, matrix metalloproteases (MMPs) are responsible for the proteolytic modification of the extracellular matrix, a complex network of polysaccharides and proteins secreted by cells that serves as a structural element in tissues and also influences their development and physiology. While more is being learned about the multiple functions of MMPs –, many of which are beneficial – their roles and biological functions are not fully understood. David Rodriguez’s research seeks to unravel the complex web of connections among MMPs, their natural substrates, inhibitors and other proteases. He is using a technique known as Mass Spectrometry to detect and identify hundreds, even thousands, of proteins in a sample. By identifying and describing the complex set of signaling pathways in which MMPs are involved, Rodriguez is hoping to better understand the role of these proteases and to predict the consequences when they function abnormally. Such knowledge is critical for designing more effective drugs to treat diseases which result from abnormal protease function.
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Regulation of lymphocyte activation and proliferation and synthesis of pro-inflammatory cytokines by the Caprin-1/G3BP-1 heteromeric complex
To fend off infections, our immune system has evolved effective strategies. These include rapidly increasing the number of infection fighting immune cells, including cytokines that promote an inflammatory response to destroy harmful bacteria, viruses and other infectious agents. The key to the effectiveness of this strategy is striking a balance between creating an inflammatory response sufficient to destroy the infectious agents without causing severe damage to the surrounding tissues. In some cases, poorly controlled or misdirected immune responses cause long term damage and disease, including arthritis and asthma. Samuel Solomon is studying how the body regulates the immune response, in particular the role of RNA binding proteins such as Caprin-1 and G3BP-1 in the process. Caprin-1 and G3BP-1 are thought to be key players in the signaling process, which controls the action of inflammatory cytokines. Solomon is studying how they affect the production of cytokines and what are the effects when these proteins are absent or functioning abnormally. This research will contribute to our understanding of immune function, which could lead to the design of novel, better and more effective cures for infections and auto-immune diseases.
SPARC in the repair of the central nervous system
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 isn’t 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 “extracellular matrix,” 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.
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. Wang’s 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 world’s languages. Weikum is testing infants’ 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 infants’ 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 – the portion of the cell outside the nucleus of eukaryotic cells. It’s 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 patients’ 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 patient’s 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 patient’s 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 Andrusiek’s 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. Andrusiek’s 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 patients’ 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.