MicroRNAs (miRNAs) are small RNA molecules that regulate the expression (activation) of genes. Recent studies of miRNA expression implicate these molecules in early development, brain development, cell proliferation and cell death. They are also implicated in disease states, such as chronic lymphocytic leukemia. Determining how, when, and where miRNAs are produced and function in cells and tissues would have profound impact on medical disciplines ranging from embryology to cancer diagnosis and therapy. The genes expressed in miRNA differ between developing and mature tissues, and comparing normal tissues to tumour tissues also reveals different miRNA expression profiles. Further studies looking at differentially expressed miRNAs could help identify those miRNAs involved in human cancer development. Unfortunately, traditional expression profiling techniques are laborious, costly, slow, or lack the sensitivity to effectively screen populations of cells and quantify miRNA content. A promising approach to overcome these limitations is the use of microfluidics technology. This technology involves constructing small chips with thousands of fluid-filled chambers, which can each contain a single cell. This reduces the number of cells used and the cost of each experiment, and allows thousands of experiments to be performed on a single chip simultaneously. Adam White is developing a microfluidic device capable of inexpensive miRNA expression profiling of many single cells at the same time. Upon successful development of this new microfluidic tool, he will work with other scientists to look for differentially expressed miRNAs in blood related cancers such as acute myeloid leukemia. The development of a microfluidic device for single cell analysis of miRNA would greatly accelerate the identification of those miRNAs involved in cancer development, and ultimately improve methods of cancer diagnosis and treatment.
Research Location: University of British Columbia - Point Grey
The immunomodulatory effects of host defence peptides on dendritic cells
Modern day vaccines are effective at preventing infections such as tetanus, influenza, polio and many others. To ensure full protection from illness, some vaccines require more than one immunization. This is commonly known as a booster shot. In developed countries, getting vaccinated usually means nothing more than going to the clinic. In developing countries the process is not so straight forward. Limited access to, and availability of vaccines makes widespread immunization a difficult process. The fact that people may have to return for a booster shot only compounds the problem. For all of the above reasons, there is clearly a need for improved vaccines in developing countries. Our laboratory is studying ways to create effective single-dose neonatal vaccines for developing countries. This means the vaccine would be given shortly after birth, and there is no need for a booster shot to ensure complete protection. Such a vaccine would alleviate the previously described difficulties. Specifically, our lab is developing more effective vaccine adjuvants. An adjuvant is simply any component added to a vaccine that will interact with the immune system to improve protection. We believe that a class of proteins known as host defence peptides (HDPs) will act as effective vaccine adjuvants. HDPs are short proteins, found almost ubiquitously in nature (microorganisms, insects, plants and mammals for example). Historically, the function of HDPs has been primarily to kill invading bacteria and viruses. Recent research conclusively shows that some HDPs are capable of altering the way in which immune system responds to an infection. My research will focus on how HDPs interact with and important type of immune cell known as a dendritic cell. Dendritic cells (DCs) circulate in the body in an “”immature”” form. When they encounter anything foreign (for example, bacteria or viruses), they become “”activated,”” capture the invader, and alert the immune system so it can mount a full response. They are now said to be “”mature.”” For this reason, DCs are a very unique type of cell. They are part of the front line of defence, yet they are also critical in generating the full immune response, which develops shortly after. We believe that HDPs will influence DCs in such a way that they will promote an efficient immune response in the context of vaccination. I hypothesize that HDPs impact DC function, activation, and maturation by altering specific genes and proteins important to DCs. This hypothesis has lead me to develop five goals to guide my research. I will provide an overview of these goals: 1) Bioinformatics. My preliminary experiments have tracked how HDPs influence the expression of 16,000 genes in mouse DCs. Such a large amount of data needs to be handled by a computer. Using specially designed programs, I am able to sort through the vast amounts of data and determine the broad trends occurring in response to HDPs. Furthermore, I am able to look at how small groups of genes behave in the context of their larger gene families; 2) IRAK-4. Results show that one peptide altered the behaviour of an important protein called IRAK-4. IRAK-4 is known to be important for specific immune responses. I will further analyze how this protein functions in the presence and absence of HDPs and other immune stimuli in DCs. I will also determine how proteins related to, and dependent on IRAK-4 will behave in response to HDPs; 3) Lyn Kinase. Another interesting finding was the altered production of Lyn, another protein important for proper DC function. I will continue analyzing the behaviour of Lyn in DCs in response to HDPs. I will also study the consequences of Lyn deficiency and determine its effects on HDP function. 4) DC Type. There are different types of DCs depending on where in the body you look, each performing similar, yet distinct functions. Currently it is not known how different types of DCs respond to HDPs. A lot of DC research is done with mouse DCs because they are relatively easy to generate compared to their human counterparts. The comparative responses of human and mouse DCs to HDPs are not well understood. For these reasons, I will be experimenting in multiple DC types, and in both human and mouse DCs. 5) In vivo peptide effects. Using the previously described experiments as a guide, I will examine how HDPs affect whole mice. We have access to mice deficient in all of the genes listed above, and this will be useful in determining the role of specific genes on the scale of a whole animal. At the completion of this project, I will have gained a comprehensive understanding of how HDPs influence DCs, with the goal of using this information to provide better vaccine adjuvant candidates aimed at developing countries.
Structural characterization of Propionibacterium acnes virulence factors
Acne is the most common skin disorder worldwide, affecting approximately 80 per cent of individuals at some point in their lives. How the skin develops this inflammatory condition is not entirely understood, nor is there a cure for severe, persistent cases of acne that often result in permanent scarring. Antibiotics are often prescribed as a first-line treatment, but the most effective antibiotic (Accutane) is known to have serious side effects, including birth defects and depression. In addition, antibiotic resistance is a growing problem. Propionibacterium acnes is present on most peopleâs skin and is the principal microorganism associated with acne. It can behave as an opportunistic pathogen under certain circumstances, expressing genes that lead to symptoms of acne. The genome of the bacterium has been sequenced and research has shown several genes that can generate enzymes for degrading skin, and proteins that may activate the immune system, leading to the initiation of acne, its development into inflammatory lesions and scarring. Angel Yu is focusing on O-sialoglycoprotein endopeptidase, a skin tissue-degrading enzyme. In order to understand how this protease works and how it recognizes its protein targets, she is growing crystals of the enzyme and using X-ray crystallography to study its structure at the atomic level. She will conduct studies that confirm the enzymeâs biological function and identify associated amino acid residues. Ultimately, Yu hopes her findings will provide insight into the molecular mechanism of this inflammatory skin disorder and identify new leads for the treatment of acne.
Video games can be good for you: an investigation of why games can be good and how to enhance their health benefits
In addition to video games being an enjoyable pastime for many people, research is increasingly indicating the beneficial effects of video game use on various cognitive abilities. Studies have demonstrated that in comparison to people who donât play video games, âgamersâ are typically better at focusing their attention and multi-tasking, and they demonstrate superior spatial processing and faster reaction times. A growing amount of anecdotal evidence suggests that video games could have health benefits, such as the use of video games as rehabilitation for stroke patients, or for improving the speed and accuracy of surgeons performing laparoscopic surgery. Although previous work has identified that video game use can lead to enhancements in attentional processing in the brain, research to date has been limited to studying how the brain orients its attention to tasks without considering the role of eye movements in this process. Joseph Chisholm is using video games to investigate the attentional differences between game players and non-game players. He is focusing on the use of âdistractorsâ â objects or events that attempt to capture an individualâs attention and distract from the task at hand. He will compare the ability of game players and non-game players to control what they pay attention to by measuring reaction times and eye movements. In identifying the mechanisms underlying how gaming enhances attentional control, this research could yield potentially novel and specialized treatment options for individuals with deficiencies in attentional processing, such as stroke patients.
Spatial modulation of vestibular reflexes by the cerebellum characterized in healthy volunteers and spinocerebellar ataxia patients
While maintaining balance appears effortless and relatively simple, it depends on a complex integration of sensory and motor signals that originate from a variety of sources in the body. When you turn your head, even though the vestibular organs of the inner ear change their orientation relative to the body, they still provide information which can be used to aid balance. This response relies on information received from vestibular organs (which measure linear and angular acceleration of the head) and sensory information from the neck (which conveys the headâs position). These two signals are then integrated to provide contextually specific directional information to the brain. As such, patients with damage to their vestibular organs tend to be posturally unstable. The cerebellum has emerged as a potential contributor to the convergence and interpretation of vestibular and somatosensory information in the brain. Patients with cerebellar dysfunction often exhibit similar abnormal balance behaviour to those with vestibular damage. Christopher Dakin is investigating the cerebellumâs role in the vestibular systems influence on balance. He is comparing postural responses associated with vestibular activation among two groups: healthy people, whose cerebellar function is temporarily inhibited by a technique called Transcranial magnetic stimulation; and individuals with spinocerebellar ataxia, a neurological disease marked by atrophy (wasting) of the cerebellum. By increasing our understanding of the human nervous system as it relates to cerebellar processing of vestibular information, Dakinâs research will contribute to more accurate balance disorder diagnoses and treatments. Ultimately, his work could lead to improved therapeutic and rehabilitative techniques directed towards patients with vestibulo-cerebellar dysfunction.
Can intrapulmonary arteriovenous shunting explain exercise-induced arterial hypoxemia in women?
The cardio-respiratory system (heart and lungs) is efficient in maintaining oxygen and carbon dioxide levels in the blood most of the time. However, during very strenuous exercise, the cardio-respiratory system may become less efficient in maintaining equilibrium of these gases. Known as exercise-induced arterial hypoxemia (EIAH), this condition is characterized by a reduction in oxygen levels in the arterial blood, starving muscles of oxygen and impairing exercise capacity. In men, EIAH has been found to be prevalent mainly in highly-trained endurance athletes at near maximal exercise intensities. However, research has demonstrated that women who are not highly trained may experience EIAH, and at lower exercise intensities. This may be due to anatomical differences: women have smaller lungs, airways, and surface areas for gas exchange relative to men. One potential explanation for the EIAH phenomenon is through intrapulmonary arteriovenous shunting, where instead of taking its normal route through the lungs to gain oxygen, deoxygenated blood from the veins is diverted directly back into the heart. This results in lower oxygen levels in the arterial blood and less oxygen available for the working muscles. Research suggests that intrapulmonary arteriovenous shunting exists in healthy, exercising humans. Jill Kennedy is conducting the first systematic study of whether intrapulmonary arteriovenous shunting accounts for EIAH observed in women during exercise. She will also explore whether this relationship is influenced by fitness. Kennedyâs research will shed new light on female physiological responses to dynamic exercise with respect to the pulmonary system. Ultimately, this knowledge could lead to the establishment of scientifically-based, gender-specific exercise prescription guidelines for women throughout their life span.
Exposure to asbestos in the slums of a sub-population of migrant ship dismantlers in Bangladesh
âShipbreakingâ is the dismantling and recycling of obsolete vessels, their hulls and superstructures. In Bangladesh, this work is carried out on beaches. Salvaged items are resold in local markets and workers and their families live in adjacent slums. Ships often contain hazardous substances such as polychlorinated biphenyls, heavy metals and asbestos, which are all recognized carcinogens. Most work is done without adequate training or protection, and there is high potential for exposures to toxic materials in the shipyards, shops and the community itself. According to the International Labour Organization, shipbreaking is one of the worldâs most dangerous occupations. On average, one worker dies every week; the long-term consequences of mortality due to cancer and other chronic illnesses are unknown. Few studies have been performed in Bangladesh on the environmental impact of dismantling ships, the health of shipbreakers, or the impact on the surrounding community and maritime environment. Working in collaboration with local university and non-governmental organization researchers, Midori Courtice is measuring the concentration of asbestos in workersâ living quarters, in shops selling salvaged items, and in areas downwind of ship-dismantling operations. She will interview people about their knowledge, attitudes and practices with respect to their handling of, and hazards associated with, asbestos. Courticeâs findings will be made available to the participants and the local community, and her recommendations could inform local workshops on hazards and reducing risk. Her work will also provide the basis to approach policy makers and strengthen the link between research and policy, to raise awareness of personal health and safety among workers, and to build local capacity for future research on sustainable solutions related to the shipbreaking industry.
Group diversity and exercise adherence in older adults
Regular exercise is associated with many health-related benefits including improvement in heart and lung functioning, sleep patterns, and mood. Improving health through physical activity also decreases the demand placed on the health care system. Unfortunately, adhering to an exercise program can be very difficult, particularly for older adults. Older adults face more chronic health problems, are more susceptible to social isolation and withdrawal, and are more likely to be hindered by age-related stereotypes regarding physical activity. Given the gradual population shift of the âbaby boomersâ into this age group, the importance of enhancing the adherence of older adults to exercise programs becomes acutely apparent. Research has sought to examine what social and environmental factors are likely to engage and sustain the involvement of seniors in physical activity. Studies suggest that older adults prefer to exercise with others of a similar in age, and generally dislike exercising in groups composed of young and middle aged adults. Although the perceived age of others may be one important characteristic, it is likely that other perceptions of the group environment may similarly influence older adults’ motives and exercise adherence behaviours. William Dunlop is further exploring the relationship between older adults’ perceptions of group member characteristics and their subsequent motivation and adherence to group exercise programs. He will study exercise groups at community and health centres across British Columbiaâs lower mainland, characterizing them by the surface-level traits of the group (age, gender, ethnicity) as well as the deep-level traits of members (e.g., attitudes, beliefs and values). By identifying how the composition of exercise groups influences the adherence behaviours of group members, Dunlop hopes his work will contribute to the development of intervention-based studies that more effectively increase the physical and psychological health of older adults.
Neurological diseases and the construction of meaning
Huntingtonâs disease (HD) and amyotrophic lateral sclerosis (ALS) are both progressive, fatal neurological diseases that together affect 6,000 Canadians. HD is associated with mental and physical deterioration, while ALS is associated primarily with physical deterioration. While there is a longstanding body of literature on the biomedical aspects of HD and ALS, there is little literature or knowledge regarding the experiences of people afflicted with these diseases. HD and ALS may progress in a manner that is unique compared to other non-neurological illnesses. Individuals can receive a diagnosis and then wait years or decades before the severe effects of the disease become apparent. During this time, these individuals are paradoxically ill in concept, but are still physically healthy and can lead comparably normal and productive lives. Michael Halpin is studying how these individuals experience knowing they are seriously ill prior to the development of the most severe symptoms, and how this affects they way in which they view health and their lives. Comparing and contrasting the experiences of people with HD and ALS, he will explore how this period of impending illness influences individualsâ perception of their health and how they view their lives as meaningful after diagnosis. Halpinâs research will improve our current understanding of individuals with these illnesses and give health professionals and researchers greater sensitivity to the concerns of these populations and their unique quality of life issues. Ultimately, this knowledge could help ensure that medical treatments and services are well suited to their experiences and needs.
The role of the spouse in pain and disease course among persons with rheumatoid arthritis
Rheumatoid arthritis (RA) is an incurable autoimmune disease that affects approximately one in 100 Canadians. It is associated with a variety of distressing and debilitating symptoms including chronic pain, stiffness and inflammation of the joints, fatigue, and frequent mood changes. As a result of their disease and related distress, persons with RA (PWRA) typically experience a wide range of daily stressors, such as difficulties performing household chores, impaired ability to work or hold a job, difficulties engaging in leisure or social activities, and interpersonal tensions resulting from added burdens for friends and family members. Although biomedical factors prompt the initial pain symptoms, psychological and social factors appear to play a significant role in the severity and course of the disease over time. For example, social support from family and friends and effective coping strategies may help to decrease pain and increase functional ability of PWRA. A relatively unexplored component of this phenomenon is the role of the spouse, who is most often the primary caregiver for PWRA . Mark Lam is investigating the relationship between the well-being and mood of the spouse and the level of support they provide to the RA patient. He seeks to answer the impact of spousal support on the RA patientâs well-being and symptoms and course of their disease. Findings regarding the role of the spouse and the social support they provide will help inform families, friends, and health care providers as to the most beneficial ways in which to respond to patients suffering from RA, helping them cope more effectively with their pain and disability.