Yeast oxysterol binding proteins and the cholesterol dependent regulation of Rho-GTPase mediated polarized cell growth

Heart disease is the leading cause of death for Canadians. More than one million Canadians currently live with this chronic disease and every year, more than 81,000 die. A major contributor to heart disease is cholesterol. Ironically, even though too much cholesterol is bad for our health, it cannot be completely removed from our bodies because it is essential for human life. Controlling dietary cholesterol is not always enough to reduce cholesterol levels in the body since our cells can also produce their own cholesterol. Loss of cholesterol regulation in our bodies not only leads to heart disease, it is also causes problems inside cells that can lead to other disease states. In fact, recent studies showed that the use of cholesterol-reducing drugs not only lowered cholesterol, they also decreased the incidence of breast cancer in Canadian women by 74 per cent. Recently, a group of cholesterol-binding proteins were identified and have been shown to mediate many of the functions linked to cholesterol. Gabriel Alfaro is using microscopy, biochemistry, and genetics to determine the mechanisms underlying how these proteins affect cholesterol regulation and mediate cellular functions. His research uses baker’s yeast as a model system, since the regulation of cholesterol in yeast is similar to its regulation in humans. Gabriel Alfaro’s research will enhance our understanding of the role cholesterol plays in the cell, and potentially point to new drug targets that could have fewer side effects relative to the current broad spectrum cholesterol inhibitors. Furthermore, his research will help elucidate the mechanism underlying cholesterol-related diseases

Studies toward the total synthesis of the analgesic natural product chimonanthine and its analogues

A major area of concern for Canada’s health system is the treatment of chronic pain, which affects more than 18 per cent of Canadians and costs the health system close to $10 billion per year. More people are disabled by chronic pain than cancer or heart disease. New structurally-novel analgesics (painkillers) with unique modes of action have proven promising. One class of these molecules are the pyrrolidinoindolines, which are alkaloids (naturally occurring compounds produced by living organisms, many known for their medicinal properties). The alkaloid (-)-chimonanthine has recently been extracted from the leaves of the wintersweet, a flowering plant originating from China. This compound has been found to exhibit analgesic effects. Unlike other opiods, such as cocaine, heroin, morphine, and codeine, chimonanthines do not possess addictive properties. Using novel techniques in synthetic chemistry, Baldip Kang is working to synthesize (-)-chimonanthine. This work is a precursor to developing analogues for this compound – drugs that differ in minor aspects of molecular structure from the parent drug, synthesized so that they have more potent effects or fewer side effects. He’s focusing on determining the most efficient and cost-effective way to synthesize the molecules. He and colleagues will collaborate with a pharmaceutical company to test the analogues in pre-clinical trials, determining modifications to the structure that will further enhance the drug’s effectiveness. Through the efficient synthesis of (-)-chimonanthine and its analogues, Kang’s research promises new ways to treat chronic pain ailments.

Spinal cord segmentation and analysis for understanding multiple sclerosis

The spinal cord is a key component of the central nervous system, acting as a relay to convey information between the brain and the rest of the body. A number of diseases affect the spinal cord, including multiple sclerosis (MS). MS affects more than 240 Canadians per 100,000, and is suspected of shrinking the spinal cord. In fact, recent studies have shown a strong correlation between spinal cord atrophy and disability related to the advancement of the disease. Spinal cord analysis, conducted with magnetic resonance imaging (MRI), is an important tool for detecting and measuring disease progression. This requires cross-sectional segmentation of the image, where specific points that correspond to the spinal cord are identified and measured over time. Most current methods require some manual intervention by radiologists; this is time-consuming and increases variability in the measurements. Chris McIntosh creates software for accurately analyzing tubular structures in the body – such as blood vessels and airways – using MRI and computed tomography. His current focus is on employing MRI to accurately measure and analyze spinal cord atrophy in patients with MS. Building on a preliminary study on automatic spinal cord segmentation, McIntosh is fine tuning the technology through additional validation, ensuring the results correspond with clinical measurements. He will then segment larger data sets with minimal user-interaction and perform analysis to see if the findings correlate with disease progression. A fully-automatic, computerized system would reduce variability seen with manual intervention, resulting in more accurate and useful spinal cord analysis. It also has the potential to free up radiologists’ time for other clinical work.

The role of active participation in the development of perspective taking in children with and without autism

Autism and its related disorders are characterized by widespread abnormalities of social interactions and communication, as well as severely restricted interests and repetitive behaviours. These disorders are described as lying on a continuum of severity, referred to as the autism spectrum, reflecting the diversity of symptoms in children with autism. Studies indicate that one major commonality among children on the autism spectrum is an impairment in their understanding of other people’s perspective or point of view. This ability is seen as the major underlying process in children’s overall social functioning. Newly-developed theories of how children typically develop perspective taking have provided important insights for assisting children with autism to improve their social understanding. However, while intervention programs are aimed at improving children’s social competence through increasing their ability to understand someone else’s point of view, the underlying mechanisms and effects on children’s ability to reason about other people’s perspectives are not well researched. Theo Elfers is investigating how perspective-taking develops by focusing on a specific aspect of social cognition — the role of children’s active engagement in perspective-taking tasks. Studying both children with and without autism, Elfers is giving the children structured tasks that allow the child to take both perspectives in a social exchange (e.g., gift giver and gift receiver), while allotting enough time for the child to remember each perspective and prompting the child to anticipate the other’s perspective. Ultimately, this work should provide researchers and mental health professionals with insights into how perspective-taking develops, and also increase the effectiveness of future training programs aimed at fostering social competence in children on the autism spectrum.

Total Synthesis and Structure-Activity Studies of a New Anti-Cancer Drug Based on the Natural Product, Imbricatine

With an estimated 159,900 new cancer cases and 72,200 deaths from cancer predicted to occur this year alone in Canada, the need for new cancer therapies with unique mechanisms of action is urgent. Researchers are finding a promising resource among the ocean’s estimated one to two million structurally diverse microbial species. Compounds derived from marine organisms offer great potential in the fight against cancer; in the past decade, more than 30 natural products from the ocean have entered preclinical and clinical trials as potential treatments for cancer. However, it is often not ecologically or economically feasible to extract the active ingredient by harvesting natural sources in the ocean. Synthetic organic chemistry – where molecules are engineered in the laboratory – serves as an alternative source of these compounds. Inhee Cho is focusing on the synthesis of imbricatine, a chemical originally isolated from the Pacific sea star that shows significant anti-tumour properties. The structural core of imbricatine includes tetrahydroisoquinoline, a molecular structure that is also found in many biologically active agents, including anti-tumour antibiotics and drugs that treat diseases such as asthma, Parkinson’s and other nervous system diseases. Cho is developing an efficient way to synthesize tetrahydroisoquinoine, allowing rapid access to this important class of natural products in order to obtain enough material for biological testing and chemotherapy. Cho’s work may facilitate the discovery of new lead compounds with useful pharmacological properties, potentially leading to new therapies for treating cancer

Fluorescent tracking of RNA in living cells: in vitro selection of fluorescent-dye-binding RNA aptamers

Within cells, RNA molecules perform a number of critical functions. Many of these functions are related to protein synthesis – the manufacture of various substances, including enzymes, hormones, and antibodies, that are necessary for the proper functioning of an organism. RNA molecules regulate gene expression (activation) to control cell reproduction, parent-specific inheritance and cell differentiation. They also interact with certain viruses during the establishment of viral infection. Despite recent advances in studying the dynamic interactions of proteins in living cells, where and when RNA molecules move through the cell to perform these various functions is still poorly understood. Elena Dogosheina is developing a new method to track RNA molecules in living cells as they move in and out of cell compartments. This movement will be visualized with the use of a fluorescent dye that contains microscopic magnetic beads to which RNA molecules will bind. This RNA tracking method could prove useful as a real time reporter for changes in RNA expression over space and time, and can be applied to study RNA splicing disorders and cancers involving differential expression of small RNAs. This method could also be used to study viral pathogenesis by visualizing intracellular organization and intercellular movement of viral nucleic acids in the course of infection.

Neurophysiological markers of the control and deployment of attention in healthy individuals and individuals with attentional deficits

In order to successfully interact with the world around us, we need to be able to focus our attention on a particular object or location, move our attentional focus from one location to another, and suppress distracting information. A number of areas of the brain have been identified as part of a network of brain regions that work together to accomplish these complex cognitive processes, but there is still very little known about how these brain areas work together to control attention. A number of neuropsychological disorders, including attention deficit hyperactivity disorder (ADHD), dyslexia, schizophrenia, and depression are accompanied by deficits in the ability to focus attention and suppress distracting information in the environment. These deficits appear to originate from different underlying causes within the overall network of brain regions responsible for attention. Jessica Green is working to identify the brain areas responsible for our ability to pay attention, and determining how these brain areas interact in healthy individuals. She will then use this baseline knowledge to explore the neural basis of attentional deficits. Using electroencephalography (EEG), Green is capitalizing on recently-developed techniques for localizing the neural sources of the EEG. She will determine not only which brain areas are involved in shifting our attention between locations in space, but also how the activity changes over time as these brain areas interact with one another. In particular, she seeks to determine whether dyslexia arises from changes in attentional processing and, if so, which brain areas and connections between brain areas are affected. A better understanding of the neural basis of attentional deficits will potentially aid in the more efficient and appropriate diagnosis and treatment of these deficits.

Health Innovation Design and Evaluation Research Team

In their ongoing efforts to improve health outcomes, decrease health care costs, and increase administrative efficiency, health care agencies are increasingly investing in information-based technologies (IT). Recently, the Canadian government highlighted the need for developing new methods for evaluating new health sector technologies in order to provide insight into the challenges associated with increased use of IT in health care settings. This award supports the development of a team that is researching the use of IT for epidemiological data collection (EDC), also known as e-epidemiology. The team’s goals include: identifying technological, organizational, governance and implementation challenges associated with the increased use of IT for EDC; addressing data quality issues arising from increased use of IT for EDC; and improving collaborations among researchers, decision makers and technology developers across disciplines who share an interest in e-epidemiology. The team hopes to improve the quality of evidence used in decision making about information technologies used for collecting epidemiological data in BC.

Trajectories towards self-harm, suicide, and other maladaptive coping behaviours

Borderline personality disorder is a serious mental health problem characterized by heightened emotional vulnerability and difficulty modulating emotional responses. Individuals with BPD have high rates of health risk behaviours, such as suicide attempts (75 per cent), self-harm (69-80 per cent), and substance abuse (60 per cent). Despite frequent intense emotional reactions to stressful events, people with BPD lack the skills to reduce their distress through adaptive coping methods. In an effort to reduce these unpleasant emotions and feel better, persons with BPD features often resort to maladaptive coping strategies that are quick and easy to execute (e.g., self-harm, substance abuse) but have negative long-term consequences. However, not everyone with BPD engages in these risky behaviours in response to every stressor, and the specific triggers for these behaviours are largely unknown. Certain types of emotional states (e.g., shame) and life stressors (e.g., being rejected) may be particularly linked with self-destructive coping behaviours. Kristy Walters is examining the specific negative emotions or particular stressful triggers that may be strongly associated with maladaptive behaviours such as self-harm, substance abuse, or suicide. This research will also examine whether or not these relationships among emotions, stressors, and maladaptive behaviours is unique among individuals with borderline personality disorder (BPD). A better understanding of which specific emotions constitute cause for concern, or which types of negative events are more likely to result in self-destructive behaviour, will considerably improve clinicians’ ability to evaluate their client’s level of risk and better identify those clients who are in urgent need of life-saving interventions.

Characterization of the mechanical properties of collagen using optical tweezers

The collagens are a family of more than 20 different proteins, all sharing the same basic structure. Collagen is the most abundant protein in mammals, comprising more than a quarter of the total protein in the human body. Its main role is in connective tissues, such as bone, cartilage, tendons and skin, where it is a vital structural element providing support and rigidity. Even small mutations can lead to weakened tissues, and genetic diseases such as brittle bone syndrome and osteoarthritis. Understanding the mechanical properties of collagen at the molecular level is important for understanding its role in these tissues, their formation, and their degeneration. In humans it has been found that the melting temperature of collagen – the temperature at which the molecule unwinds and separates – is very close to body temperature. The melting temperatures of various types of collagen have been found to be closely linked to the body temperature of the species in which they are present. This indicates that the thermal stability of collagen may be of great relevance to the structural role it plays. Benjamin Downing is investigating how temperature affects the collagen molecule’s strength and flexibility. He is using optical tweezers – a device that employs a tightly focused laser beam to manipulate micron-sized objects – to stretch the molecule and measure its stiffness and elasticity over a range of temperatures. This will reveal how closely the mechanical and thermal stabilities of the molecule are correlated. Downing’s research will help shed light on how the structure of a molecule gives it a particular strength and flexibility, knowledge that may be useful in the future design of artificial molecules that have specific properties. This information could be relevant in the development of biomaterials with applications in tissue repair.