Many patients with epilepsy take a drug called valproic acid to control seizures. Although the drug is generally safe, it has been associated (particularly in children) with a rare but irreversible form of liver failure that can be fatal. Despite substantial research efforts in the past 25 years, it’s not clear how valproic acid causes liver failure. Dr. Xiaowei Teng is studying liver cells treated with valproic acid to identify factors that could help explain how valproic acid causes liver failure. Results from this research will help clinicians identify which patients are under high risk of valproic acid associated liver damage. The findings could also serve as a model for preventing similar side effects caused by other drugs.
Year: 2004
Aminotransferase abnormalities and Multiple Sclerosis
Multiple sclerosis (MS) is thought to be a chronic autoimmune disease of the central nervous system, which attacks myelin, a protective material that insulates nerve fibers in the brain and spinal cord. Over time, MS can cause loss of balance, impaired speech, extreme fatigue and problems with vision. Currently there is no cure, but treatment with beta-interferons (IFNBs) is available to reduce the frequency of MS attacks. After a MS patient treated with IFNBs and other medications developed liver failure, Dr. Helen Tremlett initiated research examining liver function in patients treated with beta-interferons. The research revealed that 20 to 40 per cent of MS patients treated with IFNBs developed liver enzyme abnormality.
Now Dr. Tremlett is extending her research to also investigate MS patients treated with other drugs. Since many MS patients take multiple medications, her goal is to determine whether use of other drugs increases the risk of liver injury associated with IFNBs. She is also interested in determining if MS patients taking medications other than IFNBs developed liver damage. The research could provide insights about whether people with MS are at greater risk of liver injury, and whether IFNBs are the likely cause.
Identification and functional characterization of actin-related proteins associated with Salmonella containing vacuoles
Salmonella bacteria cause a number of serious illnesses, including typhoid fever, which kills over 600,000 people worldwide every year, and gastroenteritis. When Salmonella bacteria infect human cells, they use the cell’s proteins for their own survival. To accomplish this, the bacteria form a protected area within the host cell that allows them to survive and multiply. A major protein surrounding that protected area is called actin. Dr. Julian Guttman is investigating what other proteins interact with actin and how they affect Salmonella bacteria’s ability to cause disease. The research could provide the foundation for creating Salmonella vaccines or other drugs to eliminate Salmonella-based illnesses.
Processing subthreshold synaptic activity in cerebellar Purkinje cells: a role for T type calcium channels
Nerve cells transmit signals to each other across tiny gaps called synapses. The Purkinje nerve cell receives 150,000 to 175,000 synaptic signals from other nerve cells through synapses that are thought to be major storage sites for information needed to coordinate movement and balance. Loss of Purkinje cells has been associated with numerous neurological diseases and syndromes. Dr. Philippe Isope is studying the role of these synapses in learning and memory. He is investigating how the Purkinje cell is able to select and store information from the vast array of signals it receives. Dr. Isope is also determining if the T-type calcium channel, which has been implicated in a wide range of neurological disorders, filters and ampliflies information from synaptic messages. Calcium channels allow calcium to flow into cells, which supports many cell functions. This research could reveal whether dysfunctions in this calcium channel affect signal integration in the Purkinje cell, leading to learning and memory disorders.
The importance of sensorimotor integration in the control of normal human movement
People use sensory information from muscles, joints and skin to coordinate movement. Ability to use this information to make accurate movements declines with age. Loss of sensory information typically results in awkward, unrefined movements, which is why older people are noticeably slower and less accurate in their movements than younger individuals. Dr. Paul Kennedy’s research is directed at understanding the functional changes that occur with aging. He is studying age-related changes in the nervous system by recording electrical activity in the sensory receptors of two groups: people aged 20 to 30 and older people aged 70 to 80. His research could determine whether a decline in sensory activity reduces movement accuracy in older adults. Ultimately, the results could identify how specific changes in the nervous system related to aging contribute to functional impairments.
Structural elucidation of glycosyltransferases: a target for novel antibiotics
Antibiotics have played a central role in treating bacterial infections ever since the introduction of penicillin. But these drugs struggle to maintain their effectiveness over time as bacteria develop resistance that eventually renders the medication obsolete. Consequently, there is a pressing need to develop new antibiotics. Dr. Andrew Lovering is studying the structure of bacterial proteins. Dr. Lovering aims to identify the exact three-dimensional nature of a group of proteins called glycosyltransferases, which are essential to bacterial shape and form. The research could be the first step toward engineering drugs that block the usual functions of these proteins and fight bacterial infections. In earlier research, Dr. Lovering identified the 3-D structure of an enzyme proposed for use in an anti-cancer therapy. This work contributed to the design of drugs to treat leukemia.
Identification and characterization of genes dysregulated by YB-1 during prostate tumour progression
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.
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.