While completing medical training in clinical genetics, Dr. Cornelius Boerkoel was consulted on two patients with a rare disease called Schimke immuno-osseous dysplasia (SIOD). At the time, there was little known about the disease, other than that it involved kidney failure and abnormal bone growth causing short height. Dr. Boerkoel’s early research in this area highlighted several previously unknown features of this disease, including the cause of SIOD: mutations (alterations) in both copies of a gene named SMARCAL1. He has also shown that SIOD arises from abnormal activity across most genes. Working with fly and mouse models that he developed to study SIOD, Dr. Boerkoel has created a model for studying how many small alterations in gene expression can cause disease.
Since common diseases such as atherosclerosis, stroke, endocrine dysfunction, immunodeficiency, and poor growth are all features of SIOD, this research is relevant to a better understanding of various unstudied mechanisms underlying these common diseases in the general population. To continue this work, Dr. Boerkoel will complete characterization of the function of SMARCAL1 using biochemical, fruit fly and mouse studies. He will test whether hormone supplementation might be an effective treatment for SIOD. Dr. Boerkoel will also determine whether the gene expression changes observed in SIOD are a feature in other patient populations affected with diseases also found in SIOD. This research will develop a new and unique model for understanding how changes in gene expression can predispose individuals to disease.
Lysosomes are structures that digest materials within the cell. Lysosomal storage diseases are devastating diseases caused by deficiencies of specific enzymes within the lysosomes. Mucopolysaccharidosis I (MPS I) is a progressive lysosomal storage disease that affects most organ systems. In severely affected humans, this genetic disease leads to early death because of profound disturbances to the heart, brain and other organ systems. One way to correct lysosomal enzyme deficiency is through using purified enzymes for enzyme replacement therapies (ERT). However, the current methods used to commercially produce the enzymes for ERT are prohibitively costly. Because of this, sustained financial support for ERT among affected Canadians is uncertain. Dr. Allison Kermode is exploring whether using plants as hosts to produce these human enzymes will offer a more economical way to provide ERT treatments for MPS I, as well as for Gaucher disease, another lysosomal storage disease. She will test whether plant-made human enzymes are effective as ERTs. She will also establish a plant-based system for assessing potential small molecule treatments for these diseases. Finally, in collaborative work, Kermode will test plant-made lysosomal enzymes in assays for newborn screening of lysosomal storage diseases. Some of the research will be expanded to other therapeutic proteins relevant to Type I diabetes, providing a general platform for plant production of therapeutic proteins.
Ion channels are cardiac membrane proteins that control the flow of ions like sodium and potassium in and out of heart cells, regulating both cardiac electrical impulses and the contractions associated with the heart beating. Voltage-gated potassium channels, such as the human ether-a-go-go related gene (hERG). are a class of ion channels that open and close – an action known as gating – in response to changes in the electrical potential across the cell’s plasma membrane. In the heart, hERG channels play a crucial role in regulating heart rate and rhythm. Reduced hERG channel function has been associated with loss of the normal heart rhythm and sudden cardiac death. The unique role played by hERG channels in the heart is a result of their unusual gating properties. However, there is limited knowledge about the molecular mechanisms of these gating processes and how they are modulated.
Dr. Tom Claydon is using a new fluorescence technique that he established as a post doctoral fellow that provides a real-time analysis of the protein motions that cause hERG channels to open and close. With a small fluorescent probe attached directly to the channel protein, Claydon’s team can directly study movements that occur within the channel as it opens and closes and measure the electrical current passing through the channel during this activity. Only a handful of researchers worldwide are currently using fluorescence experiments to study ion channel gating. These experiments will provide a comprehensive and unparalleled view of hERG channel function and how it is modulated in health and disease. An understanding of these processes will lay the foundation for new therapies for cardiovascular disease.
Statistics show that two per cent of Canadians aged 60-74 years, and one-third over the age of 85, suffer from Alzheimer's disease and related dementias. By 2031, more than 750,000 Canadians are expected to have Alzheimer's disease and related dementias. The social and financial costs of managing people with these conditions is significant and puts a severe strain on families and on the health system. Sadly, by the time Alzheimer’s symptoms are recognized and confirmed, there is often substantial irreversible neurodegenerative damage. Current methods of diagnosing Alzheimer’s disease are frustratingly inexact. Lacking ways to identify the onset of disease within the brain itself, clinicians instead look for telltale symptoms, such as failing memory. Even when the disease has progressed and structural changes become apparent on magnetic resonance imaging (MRI) scans, neurologists do not have tools to precisely measure how advanced the disease is, relying instead on visual inspection. Dr. Faisal Beg is trained in engineering, biology and mathematics. Drawing from international MRI databases containing the brain scans of hundreds of older adults with and without Alzheimer’s, he is taking precise measurements to pinpoint where and how brain structures change with the onset of the disease. It’s a complex analysis, made even more challenging due to the normal variations seen in brain shape, size and structure. Beg anticipates that his research will help take the guesswork out of diagnosing Alzheimer’s disease, especially in its early stages. In the longer term, it also may contribute to more accurate assessments of whether new Alzheimer’s drugs are effective in slowing or halting progression of the disease
With an aging population comes an increase in a number of diseases and conditions of the eye. A recent advance in imaging – called optical coherence tomography (OCT) – provides a non-invasive way to create high resolution, cross-sectional images of inside the eye. OCT is particularly useful in providing these images of the retina, showing cross sectional images of the various layers with resolution equivalent to a low-power microscope and better than other imaging techniques such as magnetic resonance imaging (MRI).
A new technological development called Fourier Domain (FD) OCT provides these images much more quickly than existing systems. It has also been successful in creating three-dimensional images of the retina, which were previously not possible to obtain. However, clinical use of FD OCT is limited as it generates only an image of the eye’s structures, without providing any functional information about the biological processes at play.
Dr. Marinko Sarunic’s research builds on earlier work where he successfully combined FD OCT imaging with molecular contrast capabilities to provide functional information. He is now using this technology to determine its usefulness in retinal diagnostics, the study of disease processes, and the testing of new drugs and therapies. Development of FD OCT imaging techniques will help physicians better understand and manage ophthalmic conditions, through high resolution visualization and improved minimally-invasive, image-guided procedures.
Chronic inflammatory airway diseases include asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Together, these conditions contribute to an enormous burden of death and disability worldwide. It’s estimated that 10 to 15% of 13- to 14-year-olds in Canada are asthmatic. COPD affects close to half a million Canadians 35 and older, currently ranking 12th worldwide as a cause of lost quantity and quality of life and projected to rank 5th by the year 2020. CF is the most common, fatal genetic disease affecting Canadian children and adolescents.
There is compelling evidence supporting a hereditary pattern to virtually all of the major inflammatory diseases. For example, more than 1,000 CF-causing gene mutations have been identified. Although some mutations are associated with less severe disease, patients possessing the same mutations often show great variation in disease severity and progression. Significant advances in molecular genetics make it possible to discover the specific genetic variants that determine individual susceptibility to these illnesses.
Dr. Andrew Sandford is investigating the genetic variants that cause susceptibility to asthma and COPD. He is also focused on the role of genetics in CF. He works with a unique group of patient families who have previously been involved in studies to establish the associations between their genetic variations and their disease symptoms. A better understanding of the causes of inflammatory airway diseases will contribute to better prevention and/or intervention measures and more efficient treatment strategies.
Hypertension (high blood pressure) has a direct link to aging and is a major risk factor for atherosclerosis (narrowing and hardening of the arteries over time), stroke, heart attack and chronic renal failure. All known cardiovascular diseases, including hypertension, have in common a disease called endothelial dysfunction. The endothelium is a layer of cells that line the cavities of the heart, as well as the blood and lymph vessels. With endothelial disease, these cells do not function as well. Aging is known to induce and aggravate endothelial dysfunction, suggesting that endothelial dysfunction is unavoidable. One of the hallmarks of endothelial dysfunction is a decrease in the synthesis and availability of nitric oxide, which promotes dilation or relaxation of the blood vessels. Under normal conditions, nitric oxide significantly contributes to resting vasodilator tone and works to maintain a smooth and healthy vascular endothelium.
Dr. Pascal Bernatchez has uncovered a novel molecular approach that increases endothelial function and nitric oxide availability in aged vessels, while young vessels remain unaffected by the intervention. This suggests that there may be a molecular cause for how endothelial dysfunction develops. Bernatchez’s research will contribute to knowledge about how this approach restores endothelial function in an age-specific manner, how it regulates blood pressure and how endothelial dysfunction occurs. The findings may lead to novel therapeutic avenues for the range of cardiovascular diseases characterized by endothelial dysfunction.
Impulsivity is a characteristic of human behaviour that can be both beneficial and detrimental in our everyday lives. An impulsive decision can allow us to seize a valuable opportunity, or to make an ill-considered choice that we live to regret. High levels of impulsivity are not only considered socially unacceptable, but they are a key symptom in a range of psychiatric illnesses including bipolar disorder, attention-deficit hyperactivity disorder (ADHD), pathological gambling, personality disorders and substance abuse. Understanding the neurobiological basis of impulsivity could provide valuable insight into these afflictions and potentially lead to the development of new treatment and therapeutic approaches. Dr. Catharine Winstanley is exploring the role of different regions of the brain on aspects of impulsive decision-making and gambling. One of the most commonly-used measurements of impulsive decision-making in human volunteers is the Iowa Gambling Task (IGT), in which subjects try to accumulate points by choosing from options associated with varying net gains or losses. Winstanley successfully developed a model of the IGT for use in rats, allowing her to measure their cognitive processes. She is also determining whether changing levels of brain chemicals, such as dopamine and serotonin, can affect impulsive choice, and whether these chemicals activate similar molecular pathways in neurons that can alter brain function and behaviour.
Emotional processes and higher order executive functions are governed in part by interconnected neural networks that link the amygdala (a brain nucleus in the temporal lobes) to the frontal lobes. Drug addicts, particularly those abusing psycho-stimulants such as amphetamine or cocaine, show impaired cognitive function specific to these particular brain circuits. Recent evidence suggests that the brain regions comprising this circuit may be particularly susceptible to long-term neuro-chemical, anatomical and neuro-physiological alterations following repeated exposure to this kind of drug abuse.
Building on his research as an MSFHR Scholar, Dr. Stanley Floresco's multidisciplinary research program aims to clarify the alterations in brain circuitry that occur following repeated exposure to psycho-stimulant drugs. Behavioural studies will determine how repeated exposure to drugs of abuse in animals disrupt certain cognitive functions known to be impaired in stimulant abusers, such as behavioural flexibility and decision-making. Other studies will investigate how activity in these brain circuits is altered following repeated drug exposure and clarify the cellular mechanisms that underlie the associated cognitive impairments. Investigating the changes that chronic drug abuse creates in these circuits will provide important insight into the abnormal brain function that underlies drug addiction. This could lead to development of treatments for the cognitive dysfunction that occurs with chronic drug abuse.
Cells in multi-cellular organisms such as humans are arranged in highly complex three-dimensional structures. The cells attach to their environment through cell adhesion proteins, which create a type of living scaffolding for the body. Integrins are an important type of cell adhesion molecule that attaches cells to tissues to provide structure within the body (bone, tendon, etc). Cell adhesion has varied and critical roles during animal and human development. Defective cell adhesion can play a role in a variety of disorders such as muscle degeneration, thrombosis, blood clotting disorders and cancer.
Dr. Guy Tanentzapf is exploring the mechanisms that regulate the activity of integrins, as well as the role of integrins in preventing muscle degeneration. He is studying cell adhesions with the powerful genetic and molecular tools available for the fruit fly, commonly used in genetic modeling. Understanding how cell adhesions are formed and maintained is key to understanding both normal development and disease processes where integrin function is disrupted.
