Prostate cancer is the second leading cause of cancer death in men. While curable if discovered early, many men are diagnosed after the disease has metastasized (spread) to other parts of the body. At this point few treatments are effective. Androgens (male sex hormones) regulate prostate growth and development. Removing androgens is the most effective treatment for advanced prostate cancer. However, some cancer cells eventually adapt and become androgen-independent, enabling the disease to progress. The YB-1 protein regulates two genes involved in the progression of androgen independence. Using sophisticated DNA microarray technology, Dr. Susan Moore aims to identify additional genes regulated by this protein to learn how androgen independence develops. The findings could lead to earlier diagnosis and new treatments for prostate cancer.
Research Pillar: Biomedical
A structural and biochemical analysis of protein/protein interactions in the Escherichia coli degradosome
Infectious diseases are responsible for up to a third of deaths reported worldwide. A large percentage of these deaths are directly related to bacterial infections. Bacterium that cause infections, such as E.coli, thrive because of their ability to rapidly adapt to changes in their environment. The ability to rapidly adapt stems from tight control over the expression levels of proteins within the bacterium. The messenger RNA (mRNA) is a template that codes for proteins ready to be expressed within the cell. The instability of mRNA allows E.coli bacteria to quickly change the expression levels of proteins within the cell in order to adapt and survive when it invades a host cell. E.coli employs a protein complex called the RNA degradasome to degrade mRNA for this purpose. Using X-ray crystallography (a technique for determining the 3D structures of molecules), Dr. Trevor Moraes is researching how the RNA degradasome functions. This analysis of key processes involved with disease-causing bacteria could contribute to the development of new antibiotics to fight bacterial infections.
Hyperpolarization activated pacemaker channel regulation of cardiac automaticity and rhythm during postnatal development
Cardiac arrhythmias (an irregular heartbeat) can cause heart attacks and stroke or sudden death, especially in infants. Pacemaker cells in the heart beat spontaneously, unlike other heart cells, and set the heartbeat frequency. Dr. Jacob Ross is studying the role of a critical protein, the pacemaker channel, found in these cells, which causes them to spontaneously beat and may also regulate electrical activity in other areas of the heart. In particular, the pacemaker channel may regulate the ventricle, the heart’s main pumping chamber. Dr. Ross is examining the molecular and electrical properties of pacemaker channels and investigating how adrenaline-like substances affect these proteins in the ventricle. This research could provide a better understanding of basic cardiac function, which could improve prevention and treatment of cardiac arrhythmias.
Proteasomal degradation of BACE in the pathogenesis of Alzheimer's disease
Alzheimer’s disease is the most common neurodegenerative disorder causing dementia in older people. With Alzheimer’s, brain cells shrink or disappear and are replaced by irregularly shaped spots or plaques. The amyloid beta (A-beta) protein is a central component of these plaques. A-beta is a normal part of brain cells, but is toxic in high concentrations. Dr. Yigang Tong is studying why there is an increase in A-beta proteins with some older people. He is focusing on the role of the BACE enzyme that produces this protein because he believes degradation of this enzyme is impaired, allowing the amount of A-beta to increase in brain cells. Identifying the steps involved in the degradation of the BACE enzyme could help explain how Alzheimer’s disease develops and potentially lead to new drugs to treat the condition.
Structural characterization and inhibitor design of sialyltransfersases involved in lipooligosaccharide biosynthesis of Gram-negative pathogens
Bacterial resistance to antibiotics has become a major challenge in drug development. It is thus necessary to develop novel antimicrobial therapies to combat bacterial infection. Such development would require a thorough understanding of the mechanisms bacteria employ to cause disease. Campylobacter bacteria is the most commonly reported foodborne pathogen that cause acute gastroenteritis (inflammation of the stomach and intestines) and diarrheal illness in developed countries. Almost 99% of the reported cases are caused by a specific strain, called C. jejuni. Sialic acid (sugar molecules) on the cell surface of C. jejuni mimics human gangliosides and thus camouflages the bacteria from the host immune system. Cecilia Chiu is investigating the three-dimensional molecular structure of sialyltranferases, the class of enzymes responsible for the transfer of sialic acids onto the surface of Campylobacter. Cecilia aims to understand the mechanism of these enzymes and to develop molecules that inhibit the enzymes from sialylating the bacterial cell surface. This research could ultimately lead to the development of new therapeutic inhibitors against this common human pathogen.
The development and function of self-specific CD8+ CD44high T cells
About 38 percent of women and 41 percent of men will develop cancer during their lives. These staggering numbers highlight the need for new preventive measures and treatments for cancer. The human immune system is capable of eliminating pre-cancerous cells before they get a chance to grow. Salim Dhanji is researching how this process occurs. He is focusing on the development and function of a subset of T cells that control the immune system and fight infection. Salim aims to determine the conditions that maximize the ability of these cells to kill cancer cells. He ultimately wants to develop a strategy for using the body’s own immune system to fight cancer.
Functional modulation of N-methyl-D-aspartate receptors (NMDARs) by mutant huntingtin
Huntington’s disease (HD) is a hereditary, degenerative brain disorder that gradually diminishes movement and memory. HD has no cure and there are no treatments that prevent or slow the disease. Symptoms appear in middle age, with death usually occurring within 20 years as cells in specific parts of the brain slowly die or stop functioning properly. Mannie Fan is investigating the function of the huntingtin protein that causes HD, and also the molecular mechanisms that underlie development of the disease. Studies show that the death of brain cells associated with HD may result from too much activity in molecules called NMDA receptors, which normally facilitate brain cell communication. Mannie is investigating the underlying mechanisms that contribute to this increased activity. The research could help explain why people with the huntingtin protein develop HD and possibly lead to novel strategies for treating or preventing the disease.
Computational prediction and analysis of subcellular localization of bacterial proteins
Jennifer Gardy’s research is directed at predicting the location of proteins in disease-causing bacteria that could be targeted as potential vaccines or antibiotics. Jennifer developed PSORT-B, a software program that examines the biological features of proteins to predict where they most likely reside. It is the most precise software currently available for this purpose. Using data mining techniques that help establish relationships and identify patterns, Jennifer is fine-tuning the software to make it more accurate in predicting protein locations and functions. She is also developing modified versions of the program for specific groups of bacteria. Her aim is to make PSORT-B the leading software program for identifying vaccine and antibiotic targets.
Identification of novel genetic alterations in Lung Carcinogenesis
Lung cancer is the leading cause of cancer death in North America, with less than 15 percent of people surviving five years after diagnosis. The prognosis is poor because there are no symptoms in the early stages of lung cancer, which often results in the disease going undiagnosed until it is too late for established treatment to be effective. To increase the survival rate, diagnosis and treatment must occur earlier. Cumulative genetic changes are believed to cause cancer. Several genetic alterations have been identified in tumours, but the genes that lead to lung cancer remain unknown. Cathie Garnis is examining genetic changes in pre-malignant tumours to identify genes that play a significant role in lung cancer progression. The results could improve understanding of the biology behind lung cancer, and ultimately help clinicians diagnose the disease earlier and develop more effective treatments.
Relevance of aberrant activity in the temporal lobes during development to cognitive and behavioral impairment: a potential animal model of schizophrenia
People with schizophrenia experience symptoms such as delusions, hallucinations and disturbances in thinking, and often become fearful and withdrawn. Determining the cause of schizophrenia is difficult due to the heterogeneous nature and complexity of the disorder. Current theories suggest abnormal development in brain regions that regulate movement, emotion, speech, behaviour, learning and memory may cause schizophrenia. John Howland is studying whether altered interactions involving dopamine and glutamate — chemicals that carry messages between brain cells — can result in behaviour that is consistent with schizophrenia. This research could provide support for theories that developmental abnormalities cause schizophrenia.