Year: 2011
Mechanisms underlying protective effects of HDL and ABCA1 in beta cell survival
Diabetes is a major cause of disease and death in BC. According to a report from the Canadian Diabetes Association, 7 percent of BC residents currently have a diagnosis of diabetes, and this number is expected to rise to more than 10 percent by 2020, by which time diabetes-associated heath care costs in BC are expected to rise to $1.9 billion per year. Diabetes and cardiovascular disease are intimately related, and having one of these diseases is a strong risk factor for the other. Altered blood cholesterol levels increase the risk of developing both cardiovascular disease and diabetes. Blood cholesterol is carried in two types of particles: low density lipoprotein (LDL) particles and high density lipoprotein (HDL) particles. The HDL is known as the “”good”” cholesterol, as it removes excess cholesterol from tissues and is therefore considered to be protective in the development of cardiovascular disease and diabetes, and people with low levels of the good HDL cholesterol have an increased risk to develop these diseases. Dr. Willeke de Haan is working to understand how these diseases are related at the molecular level. She is specifically examining the interaction between HDL and two cholesterol transporters, ABCA1 and ABCG1. Previous studies have shown that ABCA1 and ABCG1 are both involved in insulin secretion in cells of the pancreas; this provides insight into how HDL cholesterol influences and may contribute to diabetic metabolism. Her research involves both cultured beta cells, a type of cell that secretes insulin from the pancreas, as well as various mouse models of diabetes. Using these models, Dr. de Haan will determine how altering HDL cholesterol levels contributes to diabetes development by analyzing inflammation, stress, death and markers for underlying mechanisms. Her work will also provide essential insights about the function of HDL, ABCA1 and ABCG1 in the development of diabetes and cardiovascular disease, and will validate these molecules as potential targets in the development of novel therapeutic approaches to these diseases.
Adherence to Immunomodulators in Multiple Sclerosis: Prevalence and Clinical Impact (The AIMS Study)
Taking prescribed medications as intended, or “”adherence”” is an important strategy for the management of chronic diseases. Half of the individuals with a chronic disease have poor medication adherence, and research has shown that people with poor medication adherence often have more health problems, higher hospitalization rates and a higher risk of death. Not surprisingly, medication non-adherence is extremely expensive, and is estimated to cost the Canadian health care system $8 – 10 billion every year. With an estimated 75,000 Canadians affected, and three new people being diagnosed every day, Canada has one of the highest rates of MS in the world. Multiple sclerosis (MS) is a chronic disease of the brain and spinal cord, leading to disability, severe fatigue and coordination problems. Although there is no known cure, immunomodulatory drugs (IMDs), are now commonly prescribed for MS and can lead to a substantial improvement in the health of people with MS. The benefits of IMD therapy might not be realized in people who have poor adherence; currently very little information is known about adherence to these medications. Dr. Charity Evans is working to determine how many individuals with MS have good adherence to these medications, and if people with poor adherence have higher rates of hospitalizations or worsening of the disease. She will also work to identify any time periods during therapy when an individual is more likely to be non-adherent to their IMD. Dr. Evans will be using administrative health data from three provinces (British Columbia, Saskatchewan and Manitoba), and will be studying those individuals with MS who have received an IMD between 1995 and 2008. The results of this research study will be important to determine the impact that non-adherence may have on patient health outcomes in MS, and will also help identify factors to optimize adherence to MS therapies. These methods will also be applicable to the study of adherence in other chronic diseases requiring similar drug therapies.
Analysis of the influence of retroelements on activation of oncogenes in primary human lymphomas using high-throughput sequencing
Endogenous retroviruses (ERVs) are viral DNA sequences that have repeatedly inserted themselves through the course of primate evolution and in turn become an integral part of the human genome. The human genome contains more than 200 families of ERVs, which together comprise approximately 8 percent of our chromosomal DNA. A growing body of evidence indicates that ERVs have been a major player in molecular evolution and continue to impact the mammalian genome by acting as insertional mutagens, inducing DNA rearrangements and altering gene regulation. Given the potential for harmful effects, it is not surprising that mammals have evolved multiple lines of defense against these endogenous retroviruses, such as modifying the DNA or chromatin structure to prevent the genes from being expressed. In theory, if the ERVs are de-repressed, they could become active and then cause disruptive events leading to cancer. Although the structure, function and impact of human ERVs (HERVs) on the human genome has been studied in detail, their potential contribution to cancer has not been systematically examined. Dr. Mohammed Mahdi Karimi will be applying his experience in bioinformatics methods and high-throughput epigenetic analyses to study HERV families in human cancers. He will examine gene expression patterns and different types of epigenetic modifications, including histone modifications and DNA methylation, in primary lymphocytes isolated from lymphoma patients as well as in cell lines. By identifying the epigenetic changes in the genomes of HERV families, he hopes to determine how abnormal gene expression leads to the development of human lymphomas. Dr. Karimi expects that the results from this initial analysis will reveal genes that are misregulated in cancer as a result of the de-repression of HERVs, and this misregulation will be reflected in changes to the DNA or chromatin modification. The ultimate goal of Dr. Karimi’s research is to identify molecular or epigenetic pathways that are perturbed in different types of human lymphomas, which in turn may potentially be targeted with new therapeutic strategies.
Elucidating the functions of MCL-1 in DNA repair
Mammalian cells have developed elaborate DNA damage response (DDR) and DNA repair systems in order when to protect and repair their DNA encountering toxic agents. In tumour cells, activation of these molecular events can make tumour cells resistant to chemotherapy or radiotherapy-induced DNA damage. Therefore, decoding how the DDR and DNA repair mechanisms are controlled is very important for understanding how cells become resistant to chemotherapy and to find ways to improve conventional cancer therapies. MCL-1 is a pro-survival protein that has multiple roles within the cell and has been shown to protect cells from death. It can interact with multiple important nuclear proteins involved in DDR response. Loss of MCL-1 increases genome instability after DNA damage. These studies indicate that MCL-1 may be an important component of the DDR machinery to regulate the repair of DNA lesions. Dr. Yemin Wang is investigating how MCL-1 regulates DDR and DNA repair. He is taking an intracellular approach to understand how MCL-1 is delivered into the nucleus after DNA damage and will also use this approach to investigate how MCL-1 regulates crucial events in DDR and DNA repair machinery. Dr. Wang will also examine whether the presence of MCL-1 in the nucleus affects how the cell responds to chemotherapy and whether the role of MCL-1 in DDR affects tumor development. The results of Dr. Wang’s work will provide us with a better understanding of MCL-1 in DDR and DNA repair processes, explain its essential function in vertebrate development, and help us to design improved therapeutic interventions for cancer treatment.
Allele-specific silencing of the mutant huntingtin gene in a mouse model of Huntington disease
Huntington disease is a fatal and inherited neurodegenerative disease. It is characterized by diminished voluntary motor control, cognitive decline and psychiatric disturbance. Symptoms of the disease first appear in the thirties to fifites, with death usually occurring 15 to 20 years later. While there are still no effective therapies for this disease, recent research discoveries have provided insight into how the disease develops. The normal huntingtin gene encodes a protein that is important for neuronal health. Although everyone has two copies of the huntingtin gene, people with Huntington disease have one normal copy and one mutated copy. When a person has a mutated version the gene, the huntingtin protein accumulates within cells and engages in a variety of aberrant interactions that cause disease symptoms.
Dr. Amber Southwell is working to develop a strategy for turning off the mutant copy of a patient's huntingtin gene in order to prevent or delay the onset of the disease. Her lab has identified genetic characteristics that are more common in mutant than in normal huntingtin genes and have generated therapeutic reagents that specifically target these mutant variations. This effectively switches off the mutant but not the normal gene in cellular models of Huntington disease and results in the selective reduction of the mutant huntingtin protein.
Dr. Southwell will test the efficacy of these candidate therapeutics by measuring their ability to reduce the level of the mutant but not the normal protein in the living brains of a mouse model of Huntington disease. She will also evaluate how the therapeutic reagents influence the behavior and brain pathology of these mice. This targeted approach of selectively silencing the mutant gene while sparing the normal gene is preferable to other approaches that prevent the expression of any huntingtin protein. The normal huntingtin protein is important for neuronal health, and long-term reduction of this protein may not be well tolerated. Hopefully this targeted approach will lead to new therapies to prevent or delay Huntington disease onset.
The role of the airway epithelium NLRP3 inflammasome in asthma pathogenesis
Asthma is a respiratory disease that afflicts more than two million Canadians. Asthmatics experience both airway inflammation and changes in the airway structure, called airway remodeling, when they inhale allergens, pollutants and other insults, and this leads to an exacerbation. The airway epithelium is the first site of contact for inhaled substances and has been shown to be different in asthmatics than in non-asthmatics. In specific cells of the body, including the airway epithelium, a danger sensor called the “inflammasome” can signal as part of the immune system to produce inflammation in response to an insult. Currently, we do not know if this airway epithelium danger sensor functions differently in asthmatics than in members of the general population and if this contributes to the development and progression of asthma.
Dr. Jeremy Hirota's hypothesis is that if the airway epithelium danger sensor is present, it increases airway inflammation and contributes to development and progression of asthma. His research goal is to determine the specific mechanisms responsible for airway epithelium danger sensor activation and to find out if it is more active in asthmatics. He is using three distinct approaches for his proposed research: 1) Using lungs that have been donated for medical research, he will compare the danger sensor between non-asthmatics and asthmatics. 2) Using the same donated lungs, he will grow human airway epithelial cells and expose them to an allergen or mechanical wound and then measure the resulting inflammation. 3) He will explore the role of the airway epithelium danger sensor during periods of allergen exposure by comparing normal mice to mice with a dysfunctional danger sensor.
The increasing prevalence of asthma in Canada demonstrates a requirement for a greater understanding of mechanisms leading to disease development and for new approaches to prevent or treat this disease. This research has the potential to highlight new therapeutic targets to control both excessive airway inflammation and the development of asthma.
Mortality in children under five years of age in Uganda following hospitalization for sepsis: A prospective cohort study
The United Nations Millennium Development Goal number four commits to reducing child mortality by two thirds before 2015. However, worldwide, eight million children under the age of five die annually. The majority of these deaths occur in resource-poor countries and are a result of a condition called sepsis. Sepsis usually occurs following severe infections, when the body’s immune defences begin to cause harm, leading to death if left untreated. Most infectious diseases including pneumonia, diarrheal diseases and malaria, when severe, result in sepsis. Studies from Kenya have shown that among children admitted to hospital with a severe infection, more children die within the two-month period after leaving the hospital than during their hospital stay. While there are a number of studies regarding hospital treatment, no studies have been conducted to investigate predictors of death after leaving the hospital. Knowledge of these predictors can help to identify which children are in the high- and low-risk groups and thus enabling closer monitoring of high-risk children following discharge. These risk predictors can also be used in clinical trial design so that treatments can be developed, tested, and eventually implemented to reduce sepsis-related deaths following hospitalization. The goal of Dr. Matthew Wiens’ research is to identify predictors of child death from sepsis after leaving the hospital. To do this, he will study a group of children under the age of five who were hospitalized for sepsis at two hospitals in the Mbarara district of Uganda (the Mbarara University Hospital and the Holy Innocents Children’s Hospital). During the hospitalization phase he will collect information on a series of characteristics such as the type and severity of infection, nutritional status, maternal education, access to clean water and many other potential predictors. During the six month follow-up phase after hospitalization the health outcomes of these children will be determined. Using these predictors, Dr. Wiens along with his supervisor and team of researchers will create a scoring system that allows doctors to identify children who at high and low risk of death after discharge and intervene accordingly. Understanding the factors that are likely to influence a child’s long-term health outcome after leaving the hospital will help in the development and implementation of effective interventions to reduce childhood mortality in the developing world.
Insight into motor cortex function from in vivo imaging of individual neurons
The cortex is a thin layer on the surface of the brain where most information processing takes place. The cortex is separated into several layers. There are large numbers of neural interconnections that exist between the different cortical layers, as well as many connections with neurons of the spinal cord. In the somatosensory cortex, where the perception of touch is analyzed, there is a spatial representation of the body on its surface. The same type of spatial organization exists in the motor cortex, controlling the body's muscles; however, the spatial organization of the motor cortex is not as well defined, and this characteristic allows for more change and adaptation during learning or in motor recovery after a stroke.
Dr. Matthieu Vanni will explore the participation of independent neurons in the different layers of the motor cortex of the mouse. The mouse is a model that will be used in these studies because it provides opportunities to manipulate the genome, which will be a major asset in stages of this project. Dr. Vanni will be measuring the activation of identified neurons using two-photon microscopy, which achieves a sub-cellular resolution in living tissue. The neuronal activation in the motor cortex will be measured in response to natural movements and/or following excitation/inactivation of individual neurons of the network.
The results of this study will help to better understand the information processing of motor tasks in the brain. This knowledge could have an impact on the understanding of how the brain adapts during learning and after stroke. Furthermore, understanding these cellular aspects will have important implications in the design of therapeutic rehabilitations such as prosthetic or brain stimulation, limiting post-stroke physical disability. This project will use novel applied optical methods: two-photon microscopy and optogenetics. The exceptional resolution and specificity of these new methods will have a strong impact in many other fields as well; for example, they may be applied to study neural compensation mechanisms observed in neurodegenerative diseases such as Alzheimer's or Parkinson's.