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.
Although heart disease is a leading cause of death for men and women, sex/gender differences in the disease have only recently received attention. Evidence suggests there are sex/gender differences relating to prevalence, presentation, diagnosis, treatment and outcomes of heart disease, but little is known about the underlying causes. An emerging area of interest is the fact the magnitude of the sex/gender difference in outcomes following a heart attack (favoring men) is much greater among younger women and men than among older patients. Research in this area suggests that this difference persists even after adjusting conventional risk factors.
A leading investigator in the area of cardiac health outcomes, Dr. Karin Humphries has found in previous research that among women and men with chest pain but no evidence of heart disease, women’s outcomes are worse. Now she is focusing on two primary questions: why these women have worse outcomes than men, and what is the relevance of non-traditional risk factors, such as quality of life and psychosocial factors, in young women and men who present to hospital with a heart attack. The results of these studies will provide new knowledge about sex/gender differences and heart disease. Humphries aims to increase understanding of quality of life differences between young men and women who suffer a heart attack, which may help explain the different outcomes and help with the development of new strategies for diagnosis, treatment and support of women with heart disease.
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.
Although there are large individual differences in recovery rates from alcoholism, little is known about the emotional factors that underlie these differences. Studies suggest that shame and guilt, two negative self-conscious emotions (emotions that require self-evaluations), may have divergent effects on a range of health outcomes. Specifically, shame promotes a range of negative outcomes, such as depression, whereas guilt has more positive effects, including empathy and high self-esteem. In addition, two distinct kinds of pride — “authentic” and “hubristic” — may also have divergent effects. Dr. Jessica Tracy is researching the influence of these four emotions on recovery from alcohol addiction. She is testing whether newly-sober members of Alcoholics Anonymous (AA) who experience guilt and authentic pride, rather than shame and hubristic pride, enjoy greater health and recovery benefits over time. Tracy is also testing whether the thought processes that promote these emotions contribute to health outcomes, and if so, whether specific self-conscious emotions account for these effects. This research is unique in its emphasis on self-conscious emotions, which may play an important role in addiction. The findings could lead to new treatment methods for clinicians, such as targeting these important emotions.
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.
Viruses are responsible for many of the world's most serious diseases. In Canada, viral infections remain the single most common reason that people seek medical attention. In order to spread infection, many viruses replicate themselves in the nucleus of their host cells. To accomplish this, they must transport their genome into the nucleus – a process known as nuclear trafficking. Today, many aspects of this viral replication and initial entry into cells are well understood at the molecular level. However, very little is known about how viruses deliver their genetic material into the nucleus. Interrupting the trip into the nucleus could prevent the virus from spreading. A detailed description of this process is an important step to developing anti-viral therapy.
Dr. Nelly Panté studies the mechanism by which viruses deliver their genomes into the nucleus of their host cells. In particular, she is focusing on two common and important viruses: Influenza A and Hepatitis B virus. To investigate the trafficking of these viruses, Panté uses a combination of structural, functional, biochemical, and genetic approaches. As well, she uses high-resolution electron microscopy to track the virus’ movement and entry into host cell nuclei. This work is critical for complete understanding of viral infections – not only for targeting viral illnesses, but also for their potential application in gene-delivery technology, such as in anti-cancer gene therapy.
All successful viruses have evolved strategies to infect host cells and disrupt normal cell functions. However, the host can counteract these strategies by using its natural antiviral responses to detect and defend against viruses. Revealing the molecular mechanisms between the battle of the virus and host is vital in the fight against many of today’s viruses. Some viruses use an internal ribosome entry site (IRES) to infect cells. Molecular machines in cells called ribosomes translate genes into proteins, but viruses with an IRES can hijack the ribosome to replicate their viral proteins instead. IRESs are found in a number of human viruses, including polio, hepatitis C, herpes and HIV, but there is limited understanding of how these mechanisms work. Understanding the ways in which a virus hijacks the ribosome function is the focus of Dr. Eric Jan’s laboratory. He uses a unique IRES found in an insect virus called the cricket paralysis virus (CrPV). Jan’s previous work was critical in delineating important CrPV IRES functions. Building on this work, he plans to map the specific IRES elements that interact with the ribosome. He will also determine how CrPV disrupts cellular function that leads to IRES activity in Drosophila (fruit fly) cells, and elucidate the host antiviral response in these cells. The study of Drosophila antiviral responses will contribute to knowledge about fundamental virus-host interactions in humans. The research could lead to new drug targets for inhibiting viral IRESs and therapies that can augment antiviral responses. An exciting future goal will be to exploit viral IRESs to prompt the destruction of virus-infected cells – taking advantage of a viral mechanism against itself.
Electrical signals are the fastest signals in our bodies. These signals are mediated by ion channels, specialized proteins that allow particular charged ions to pass through cell membranes. One class of ion channels, known as voltage-gated calcium channels, is of particular importance. They allow calcium ions to pass through the cell membrane when an appropriate electrical signal is present. In doing so, these channels play crucial roles in regulating heartbeats, in muscle contraction and in the release of hormones and neurotransmitters. The role of calcium channels in human health is significant. Mutations in the channels cause severe genetic diseases, and many drugs that are currently used to treat cardiovascular diseases, epilepsy and chronic pain target calcium channels to limit their dysfunction. Efforts to develop new drugs are hampered by the limits of what is known about the channels, particularly about their atomic structure. Dr. Filip Van Petegram is working to shed new light on the intricate workings of calcium channels that are expressed in the heart, in the brain, and in skeletal muscle. Van Petegram uses cutting edge technologies to gain a precise understanding of calcium channels. X-ray crystallography determines a protein’s atomic structure, producing high resolution structural images that serve as excellent templates for the design of new drugs, and provide valuable information about how the channels work. Electrophysiology measures the tiny electric currents that are generated when calcium ions pass through the channels. This work will contribute to novel treatment strategies for targeting calcium channels.
Stroke is the third leading cause of death and the most common cause of adult disability in Canada and worldwide. Nearly half of all people with stroke do not have full use of their arms for daily tasks and seek rehabilitation to help restore their function. Recent discoveries have targeted effective treatments for individuals who are still able to move their wrist and fingers after stroke, but there are currently few therapies for individuals with poorer hand movement ability.
Dr. Lara Boyd is exploring whether learning and recovery of function can be enhanced by pairing direct stimulation of the brain with practice of a new motor task. Her research focuses on two areas: testing whether exciting the brain using transcranial magnetic stimulation (TMS) before practicing a new motor skill will promote faster learning and recovery of former motor function; and determining the effect of stroke severity on motor learning. Boyd expects that pairing brain stimulation and practice will help people with stroke learn new motor skills faster and more effectively than when brain stimulation is not delivered. This research may lead to new therapies to help people with stroke return to their regular activities of daily life. Brain stimulation using TMS may specifically offer an effective treatment for people with poor hand and arm function after stroke.
