Research Location: Simon Fraser University

Optimal functioning requires organisms to anticipate and adapt to daily environmental changes driven by the cycle of the sun. Entrainment is the process by which daily rhythms of behaviour and physiology are synchronized to the environment. Shift-workers and air travelers are often out of sync with their environment due to a mismatch between their internal clock and the external environment. This dyssynchrony leads to general discomfort and reduced performance known as shift-work malaise or jet-lag. This has a detrimental effect on health, performance, levels of productivity and quality of life. Glenn Landry aims to achieve a better understanding of the mechanisms of entrainment. In mammals, an area of the brain called the suprachiasmatic nucleus acts as a master pacemaker. In animal models that have access to food and water without restriction, damage to this area of the brain eliminates all daily rhythms. However, if food is restricted to one to two meals at a fixed time each day, these animal models are still capable of anticipating the feeding time. This shows that a separate pacemaker exists for anticipating food. But identifying this food-entrainable pacemaker has been a challenge since many brain structures are activated during food restriction, making it difficult to isolate the pacemaker from background activity. Landry is testing a recently developed strategy to filter out this background activity. By using a number of different stimuli capable of activating the food-entrainable pacemaker, he aims to isolate this pacemaker by identifying brain areas activated in common across these stimuli. Landry hopes identifying the food-entrainable pacemaker could ultimately lead to new approaches to re-setting the clocks of shift-workers and air travelers, improving health and productivity.

There is a growing prevalence of type 2 diabetes. It has been estimated that more than 20 million people have the disease in the United States alone. Type 2 diabetes is a disease characterized by resistance of our bodies to insulin, a hormone needed for normal metabolism of carbohydrates, fats, and proteins. This resistance leads to prolonged elevation of blood sugar levels, eventually giving rise to the diseased state. Understanding what events lead to insulin resistance is an intense topic of research. Nevertheless, the precise molecular mechanisms by which insulin resistance arises still require delineation in order to fully understand the disease Building on his MSFHR-funded Master’s research, Matthew Macauley is investigating what the role of proteins modified by a sugar known as GIcNAc have in causing insulin resistance. One hypothesis is that high levels of glucose over a long time period may increase GlcNAc modification and that this in turn results in insulin resistance. Macauley is using an enzyme inhibitor of O-GlcNAcase to artificially create elevated levels of GlcNAc in animal models to determine if insulin resistance and type 2 diabetes ensue. Using this same enzyme inhibitor, Macauley is also conducting a separate study to increase GIcNAc attached to tau, a key protein involved in the development of Alzheimer’s disease. The goal of this study is to determine if the inhibitor can prevent or delay the onset of Alzheimer’s in an animal model.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons (specialized nerve cells) in the spinal cord, brain, and descending motor tracts. ALS leads to muscle weakness and paralysis, and is often fatal. Numerous biochemical processes have been linked to the progression of ALS, including increased levels of protein modification (phosphate units). Xiaoyang Shan is researching the role of modified sugar units, known as O-GlcNAc, in maintaining the proper functioning of neurofilaments (structural proteins) that give neurons support and shape but become damaged in ALS patients. He is also investigating the role of O-GlcNAc in maintaining healthy motor function. The findings could help increase understanding of the causes of ALS, and contribute to development of a potential treatment to slow or halt the progression of the disease.

Parkinson’s disease is a degenerative disorder of the central nervous system. Symptoms include shaking, muscle stiffness, speech problems, memory loss and vision problems. The disease involves the inactivation of dopamine-producing cells in a part of the brain called the substantia nigra. There is no definitive test to diagnose Parkinson’s disease, making it difficult to diagnose in its early stages. By the time a patient is diagnosed, up to 80 per cent of the dopamine-producing cells may have already stopped working. There is therefore a need for a more reliable test for diagnosis of Parkinson’s disease. There is reason to believe that Parkinson’s disease can be detected by measuring the size and shape of two anatomic structures within the brain that are both connected to the substantia nigra: the caudate nuclei and the putamen. When the cells in the substantia nigra become inactive, less dopamine is sent to the caudate nuclei and putamen. Aaron Ward is studying whether a decrease in dopamine results in changes to the size or shape of the caudate nuclei or putamen. Using magnetic resonance imaging, Ward is computing a 3-D representation for each patient’s caudate nuclei and putamen. The ultimate goal is to discover aspects of the shape of these structures that could serve as indicators of Parkinson’s disease. This would allow earlier and more reliable diagnosis, and facilitate the tracking of patient response to therapy.