Schizophrenia and related forms of psychosis are among the most severe, persistent and debilitating illnesses affecting young people. A key priority in the treatment of this disease is the development of novel antipsychotic drugs to address common cognitive deficits resulting from schizophrenia, which include impairment of attention, memory and executive function. These deficits are identified as being the most serious symptoms of the disease, and the degree of severity is the best predictor of how well or poorly affected individuals will fare over the long term. Dr. Alasdair Barrâs current research is focused primarily on identifying brain cell alterations associated with schizophrenia that may contribute to cognitive deficits. His teamâs previous work has shown that levels of two related presynaptic proteins, complexin I (inhibitory terminals) and II (excitatory terminals) are decreased in the frontal cortex and hippocampus. They also demonstrated that lower hippocampal levels of complexin II were associated with cognitive dysfunction, representing the first description of a relationship between abnormal synaptic function and cognitive function in schizophrenia. Dr. Barrâs current work is building on these findings to further understand the role of complexins in cognition and schizophrenia.
Research Pillar: Biomedical
Investigating the molecular basis of collagen's finely tuned stability with single-molecule manipulation techniques
Collagen is the fundamental structural protein in our bodies, which means changes in its chemical composition can have profound, widespread effects on health. For example, connective tissue diseases, the leading cause of disability and absence from work in Canada, can be caused by a change affecting only one position out of 1000 in the DNA sequence that codes for collagen. As we age, collagens in our body tissues become chemically modified, leading to structural changes that result in weakening of bone structure and the deterioration of joints, arteries and the retina, a situation that is exacerbated by diabetes. The controlled production and degradation of collagen is important for normal embryo development; a breakdown in this controlled pathway is also associated with the spread of cancerous tumors in the body. All of these health-related problems are related to chemical changes in collagen, which lead to changes in its structural and elastic properties at the tissue level. Dr. Nancy Forde is studying the elastic properties and stability of single collagen molecules, to identify the relationship between chemical changes and changes in the structure and function of collagen. Her team is employing the worldâs smallest tweezers, optical and magnetic tweezers, to grab, stretch and twist single collagen proteins. This special equipment is currently applied to protein study at only a handful of labs worldwide. Dr. Forde and her team are directing their efforts to better understand how changes in collagen at the molecular level affect the elastic and structural properties of tissues. This research could help explain how tissues deteriorate with age, as well as the impact of these changes on the development and severity of diseases such as cancer and diabetes.
A molecular picture of the innate immune response to Salmonella: quantitative proteomic and cell biological analysis of Salmonella vacuole development
Salmonella bacteria reside in the intestines of animals and can be transmitted to humans via contaminated food or water. These bacteria cause diseases such as typhoid fever and acute gastroenteritis, posing major health problems throughout the world. The body normally produces an immune response to these invading microorganisms. In a process known as phagocytosis, the bloodâs immune cells engulf the bacteria, enclose them in specialized internal compartments, and then release destructive enzymes that kill them. However, Salmonella and several other intracellular parasites have evolved methods to subvert this process. By blocking the delivery of the destructive enzymes, these parasites avoid extermination and are able to survive and multiply inside the immune cells. Ultimately, bacteria escape from the cell and spread throughout the body to cause disease. Dr. Leonard Foster is employing advanced proteomic methods and instrumentation to explore and describe what occurs at the molecular level during phagocytosis. This research will lead to a better understanding of the basic operation of this important aspect of immune function. It will also advance knowledge of the molecular mechanisms employed by Salmonella bacteria to prevent the immune cells from delivering the destructive enzymes, potentially leading to better methods of protecting against Salmonella infection.
Understanding the role of cryptochromes in human circadian phototransduction
The human eye is much more than the organ of vision. In addition to the machinery of the eye that allows us to see, the retina also houses photoresponsive molecules (photoreceptors) that mediate non-visual, light-driven signaling pathways. Our biological clock is regulated by the input of these light signals, including the circadian (24-hour) oscillation of our biochemistry, physiology, and behaviour. Many human functions rely on circadian rhythm and its accurate synchronization with the outside world by light (circadian phototransduction), including sleep, hormone regulation and brain function. Despite its central role in human health, however, virtually nothing is known about circadian phototransduction, including the light-driven events in a key photoreceptor called cryptochrome. Dr. Melanie OâNeill aims to uncover these events and to describe the mechanism of action of cryptochromes as circadian photoreceptors at the molecular and cellular level. Her research will provide a critical link between light input and biological response, and offer the basis for a description of circadian phototransduction that rivals our detailed description of vision. This research will enable an understanding and potential manipulation of biological timing that may transform our view of human health and our treatment of a host of human diseases including sleeping disorders, depression, and cancer.
Structure-based antibiotic discovery on the bacterial membrane
The growing resistance of bacterial infections to standard antibiotic therapies is a major health concern around the globe. The microorganisms that cause serious illnesses such as hospital staphylococcus aureus infections, tuberculosis and meningitis are increasingly developing antibiotic resistant strains both within the hospital and community settings. Some particular bacterial infections, often termed “”superbugs””, have become entirely resistant to all antibiotics currently used in hospitals. Dr. Natalie Strynadkaâs research is directed at understanding the way in which bacteria resist current families of antibiotics and at developing new antibiotic drugs that work by inhibiting specific features of the bacterial life-cycle. Her research team will undertake this research by characterizing the three-dimensional atomic structures of molecules critical to the viability of the bacteria, such as their ability to âinjectâ antibiotic resistant genes into host cells. By describing these structures in fine detail, they will be positioned to design antibiotics that specifically inhibit these critical molecules of the bacteria, destroying its ability to cause disease.
Role of SPARC in cancer therapy
Colorectal cancer (CRC) is the third most common cancer in both men and women, and was responsible for an estimated 8,300 deaths in 2004 in Canada. While there has been an overall decline in the incidence and mortality of CRC in the past two decades because of better cancer prevention, the overall five-year survival rate continues to be poor. This is due in part to chemotherapy resistance, which is common in many solid tumours. Dr. Isabella Taiâs research is directed at understanding the mechanisms enabling cancer cells to become resistant to cancer drugs and other therapies. Using a high-throughput âgenomicsâ approach, her research team has developed a comprehensive list of genes involved in chemo- and radiotherapy resistance. One such gene, SPARC, had low levels of expression in colorectal cancer cells that were resistant to several chemotherapy agents. By increasing the levels of SPARC in therapy refractory cells, response to radiotherapy and chemotherapy was restored and tumor size reduction was observed. Dr. Taiâs team is now examining the general applicability of SPARC-based therapy in other cancer model systems, how it promotes tumor regression, and whether patients who are likely to become resistant to therapy can be identified based on a potential diagnostic marker. The results of the project could lead to improvements in cancer treatment and potentially provide a diagnostic marker to identify individuals likely to develop chemotherapy resistance.
Notch signaling in Lymphoid Neoplasia
A common theme in cancer is the dysregulation of a normal developmental process that either directly causes cells to grow in an uncontrolled manner, or renders them susceptible to cellular damage that, in turn, leads to uncontrolled growth. One example of this process occurs with a normal cellular gene called Notch, which is inappropriately activated in a large fraction of cases of a certain type of blood cancer called T cell acute lymphoblastic leukemia (T-ALL). During normal development of the immune system, regulated Notch activity is required for formation of mature lymphocytes that protect the body from infection. When activated, Notch promotes the formation of normal T lymphocytes, but if this signal is not turned off in time, these T cells can undergo malignant change and become cancerous. Dr. Andrew Weng is studying the signals that are generated by Notch activation and the context in which these signals are received by the cell. By understanding the role of Notch in cancer development, he hopes to develop methods for manipulating Notch activity to shut down the growth of established cancer cells, and perhaps also to prevent it from occurring in the first place.
Role of the tumor suppressive E3 ubiquitin-protein ligase, Hace 1, in the development of childhood neoplasm
The onset and growth of a tumour may be due to the destruction of the balance that is normally achieved between tumour promoting and tumour suppressing factors. Recently, Dr. Poul Sorensonâs research team discovered a new gene, Hace1, from a case of Wilms’ tumour (the most common kidney tumour of childhood). They also found that Hace1 protein levels were reduced in 75% of the Wilms’ tumours analyzed, and that the restoration of Hace1 levels in tumour cells was capable of inhibiting tumour growth. These findings suggest that Hace1 is a tumour suppressive factor and that loss of Hace1 may contribute to the development of childhood tumours. However, the mechanisms by which Hace1 inhibits tumour formation are not yet understood. Current research suggests that Hace1 is an enzyme that specifically labels target proteins with small protein tag(s) called ubiquitin. It is thought that alterations of this process, as in the reduction of Hace1 levels observed in Wilmsâ tumour, may lead to malfunctions of the target proteins and facilitate tumour development. Dr. Fan Zhang is testing this hypothesis through the identification of Hace1 target proteins and analysis of the Hace1 function in both normal and tumour cells. The knowledge derived from this study will help researchers understand how loss of Hace1 leads to the formation of childhood tumours which, in turn, may lead to new preventive treatment based on correcting the imbalance between tumour promoting and tumour suppressive factors.
Characterizing the antiviral immune response in the yellow fever mosquito, Aedes aegypti
Arthropod-borne viruses (arboviruses) are viruses transmitted to plants and animals by insect vectors, such as mosquitoes and ticks. In human and animal populations around the world arboviruses such as West Nile virus continue to cause significant morbidity and mortality. To date, research efforts around these viral diseases have focused almost entirely on humans. There is however another important aspect to the disease dynamics, which has not been addressed, and that is the effect of these viruses on the insects that transmit them. The insect immune system shares many features with the human immune system yet very little is known about how insects regulate viral infections. Research has shown that arboviruses somehow evade the insectâs immune system yet are capable of transmitting the viruses to other hosts. Dawn Cooper is examining what factors viruses use to develop in insect vectors and the factors that insects use to kill viruses. Her research focuses on characterizing the immune responses expressed in response to the virus infection of Aedes aegypti, a major vector of arboviruses. Ultimately information gained through this study will identify the novel fighting components of the insect immune response which may be exploited to reduce transmission or develop drugs to treat human infections.
New routes to sialidase inhibitors: Synthesis, characterization, and evaluation of novel sialic acid derivatives
For many people, infection with the influenza virus results in several days of illness. Yet, each year, the virus is responsible for approximately one million deaths worldwide. Vaccines are the most common preventive treatment, but they only protect vaccinated individuals against those strains identified by the World Health Organization as being the most virulent in any given season. When a new strain of influenza appears against which humans have no immunity â as occurred with the Spanish flu pandemic of 1918 (which killed 20 million people worldwide), the Asian flu pandemic of 1957, and the Hong Kong flu pandemic of 1968 â the result is a pandemic that could infect and kill hundreds of millions of people worldwide. Better treatments and preventative measures to fight influenza infection are needed to counter this threat. There are currently two major anti-influenza drugs on the market that selectively inhibit a viral enzyme that is critical to spreading infection. While these drugs are effective, the influenza virus is resilient and by mutating can develop drug-resistant strains. Ivan Hemeon is researching the development of new anti-influenza compounds that have a much lower risk of generating resistant strains. Hopefully, people treated with these compounds would experience less severe symptoms and recover faster without the risk of harbouring resistant strains that could be passed on to others, particularly those made more vulnerable due to compromised immune systems.