Proteins, the molecules that carry out many cellular functions, are synthesized according to information contained in DNA sequences. Converting information from DNA into a protein requires an intermediate step in which the DNA sequence is copied into a molecule called RNA. In humans there is an essential biochemical process called RNA splicing, in which non-coding portions of the sequence are removed and the remaining protein-coding portions are joined together to form a template for protein synthesis. Ninety percent of human genes are subject to splicing, so it is not surprising that errors in this process have been linked to a wide array of diseases, including retinitis pigmentosa, spinal muscular atrophy, cystic fibrosis, myotonic dystrophy, Alzheimer’s disease and cancer. Splicing is catalyzed by the spliceosome, a large and dynamic complex that consists primarily of five small nuclear ribonucleoproteins (snRNPs) designated U1, U2, U4, U5, and U6. During spliceosome assembly, the snRNPs interact with each other in a step-wise, ordered way. One of the first steps in assembly involves U4 and U6 pairing to form a particle called the U4/U6 di-snRNP. Although the di-snRNP complex is essential for spliceosome assembly and function, the mechanism by which it forms is poorly understood. Tara Wong is investigating the process by which U4 and U6 undergo essential conformational changes necessary for spliceosome assembly. She is using chemical modification/interference experiments to determine how free U4 and free U6 snRNPs interact to form the U4/U6 di-snRNP. This knowledge will be fundamental to understanding spliceosome assembly and function, and should ultimately lead to a better understanding, and treatment of splicing related diseases.
Year: 2008
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.
Vascular dysfunction of the arteries in a mouse model of Marfan syndrome
Marfan syndrome is an inherited disorder of the connective tissue that causes abnormalities of the eyes, cardiovascular system, and musculoskeletal system. Its most serious and deadly complication is ballooning and rupture of the aorta, the major blood vessel that carries blood from the heart to the arteries and organs. The syndrome is caused by a defect in the gene that makes fibrillin-1 protein. Fibrillin-1 is essential in the formation of elastic fibres in arteries and in maintaining the functional and structural integrity of blood vessels’ endothelial and smooth muscle cells. Defects in this gene result in abnormalities in the way vessels contract and relax, increasing the susceptibility to ballooning and rupture of the aorta. Huei-Hsin Clarice Yang is studying the effect of Marfan syndrome on endothelial and smooth muscle cells in the aorta and the small arteries. She is expanding on previous research that found that smooth muscle in the Marfan-affected aortas is unable to relax normally. Her work focuses on the mechanisms that contribute to this dysfunction within smooth muscle cells and in the epilethial cells that regulate vascular contraction and relaxation. Yang’s work will provide valuable insight into how Marfan syndrome causes decreased contracting and relaxing abilities of the arteries. Ultimately, this knowledge could lead to innovative therapies to prevent or treat aortic rupture and to halt the vascular deterioration process in patients with Marfan syndrome
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 people’s 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 enzyme’s 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.
The development of the corticospinal tract in premature newborns: impact of early brain injury and relationship with motor abilities
Approximately eight per cent of babies in British Columbia are born prematurely (less than 37 weeks after conception), and survival rates have improved dramatically for these infants. Motor and cognitive impairments are common among children born prematurely: five to 10 per cent will exhibit motor deficits such as cerebral palsy, and up to half will experience problems with brain functions (such as learning to speak). At school age, these delays in development can become greater concerns as they may interfere with learning and social interaction. Recent studies suggest that the developmental impairment observed may be associated with abnormal development of the brain regions responsible for motor and brain functioning. Early brain abnormalities, such as white matter injury (WMI), may underlie maturational impairments of these regions. A key brain pathway of interest is the corticospinal tract, which carries voluntary motor information from the control centre of the brain (the cortex) to muscles of the body. Elysia Adams is determining whether brain abnormalities, such as WMI, in premature newborns in their early life will affect their motor and brain function. Using advanced imaging techniques with magnetic resonance imaging (MRI), she is comparing corticospinal tract development among premature babies with and without these brain abnormalities,. This will allow her to determine whether WMI affects the development of the corticospinal tract and to establish whether later motor function can be predicted by assessing the tract’s development. Ultimately, this research could lead to ways to predict brain outcome among babies born prematurely. This would allow doctors to identify motor problems earlier and provide appropriate treatments, such as physiotherapy, to improve outcomes or prevent the long-term consequences of these developmental delays.
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 don’t play video games, “gamers” 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 “distractors” – objects or events that attempt to capture an individual’s 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 head’s 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 cerebellum’s 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, Dakin’s 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.
Effect of cam-type deformity associated with femoroacetabular impingement on hip mechanics
Hip osteoarthritis (OA) is a painful condition affecting 4.4 per cent of the population aged 55 and older. Currently, there are very limited treatment options and no known cure for OA. Improving prevention and treatment of early hip OA requires a thorough understanding of the joint mechanics and how these mechanics affect the initiation and progression of the disease. Hip OA can either be primary (occurs with no previously known cause) or it can be secondary to a known deformity. It has recently been hypothesized that most “”primary”” cases are actually caused by small deformities in the joint that were previously unnoticed. One deformity that has been found to have a strong correlation with hip OA is called a cam deformity, which can cause pain and decreased range of motion in the hip. Cam deformities occur on the upper femur (thigh bone) and cause increased contact between the femur and the acetabulum (hip socket). Joint contact pressure is thought to play a role in accelerating the onset of OA. To determine the association between cam deformity and the onset of hip OA, Laura Given is studying how the joint mechanics change depending on the degree of cam deformity. She will track how the joint translations and rotations are affected throughout the range of motion of the hip and determine how the range of motion is affected by simulated cam deformity. By describing how the size of cam deformity affects joint mechanics, Given’s research will help surgeons understand how to effectively correct the deformity in an effort to slow or even stop the osteoarthritic disease progression. It could also lead to preliminary guidelines in arthritis screening programs. This could reduce the number of cases of hip OA seen in the future.
The reliability and validity of the External Hostile Attributions Scale (EHAS) in a sample of civil psychiatric patients and criminal offenders
Violence, victimization, and suicide-related behaviours have many negative consequences on society and are viewed as critical public health issues. It is estimated that 2,000,000 violent crimes are committed each year in Canada, and that costs to victims, such as health services, approximate $47 billion annually (Statistics Canada, 2003). In addition to the important costs to the healthcare system, these violent outcomes greatly affect individuals’ quality of life as well as mental and physical health. Melissa Hendry’s research aims to reduce the risk of these negative behaviours by investigating risk factors for such behaviours; specifically, she is interested in hostile attributions, which is the attribution of malevolent intent to others, which she will study in a sample of civil psychiatric patients and criminal offenders. This research will assess participants’ level of hostile attributions using a new measure of hostile attributions, as well as other variables such as psychiatric symptoms, substance use, and criminal attitudes, to see how these relate to one another. Another purpose of her project is to look at the association between hostile attributions and behaviours such as violence, victimization, self-harm, and suicidal ideation and attempts. Exploring this research area to a greater degree could have far-reaching consequences in terms of decreasing the incidence of violence-related adverse outcomes in civil psychiatric patients and criminal offenders, thereby enhancing overall population health and reducing health care system costs. The results of Melissa’s research are expected to raise implications for reducing the risk of harmful behaviours in these individuals in terms of implementing new treatment and intervention programs.
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. Kennedy’s 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.