Human embryonic stem cells (ES cells) — cells obtained from an embryo when they are only a few days old — are unique because they can become any type of cell. They can also multiply in the laboratory for very long periods of time without losing this special ability. ES cells offer huge medical potential, both in research and clinical applications. They could, for example, be turned into cells affected by cancers, such as blood cells or brain cells, then genetically altered to become cancer-like and studied to identify potential drug targets or other unique characteristics. Human ES cells could also be used as a cell source for many different kinds of transplantation. One of the biggest hurdles to overcome in working with human ES cells is increasing understanding of how these cells turn into specific kinds of cells. Because they can become anything, ES cells often become many different things at once, which makes them difficult to study and potentially inappropriate for transplantation. A better understanding of the mechanisms an ES cell uses to turn into different kinds of cells would help ES cell differentiation be better controlled and directed towards cell types of interest. Building on her previous MSFHR-funded research, Melanie Kardel is researching how ES cells turn into blood cells. Kardel’s focus is on determining how many blood cells can be produced from a single ES cell, and what genes can influence either the number of blood cells produced or how long it takes to produce them. The research could contribute to more standard, controlled procedures for high efficiency blood cell production from human ES cells.
Program: Trainee
The molecular characterization of murine hematopoietic stem cell self-renewal divisions
Every day, billions of new blood cells are produced in the human body. The origin of these cells, which are produced in the bone marrow, can be traced back to a tiny population of self-maintaining cells known as blood stem cells. Drugs used in current cancer treatments cause considerable damage to these stem cells and this can prevent more effective doses from being used for treating a number of cancers. Better ways to protect blood stem cells or to increase their numbers in a controlled fashion are needed. Additionally, many types of leukemia are known to be sustained by mutated blood stem cells. More detailed understanding of the mechanisms that regulate normal blood stem cells and how they become mutated is needed to determine how leukemia arises and how the many types of the disease can be treated more effectively. David Kent and his colleagues have recently developed a technique that allows them to isolate nearly pure populations of normal blood stem cells from the many different cell types (blood stem cells are at a frequency of between 1 in 10,000 and 1 in 15,000 cells) present in the bone marrow of adult mice. They are now able to stimulate these cells to behave differently (i.e.: to give rise to a daughter stem cell or not) in short term cell culture using different growth factors. Kent is comparing the sets of genes in these purified and differentially manipulated blood stem cell populations to identify genes that are involved in the regulation of normal blood stem cell expansion. He hopes his work will facilitate further research into the controlled expansion of stem cells and other blood cell types, and offer insight into the mechanisms by which stem cells mutate and replicate as cancer cells. He also hopes to expand fundamental knowledge of stem cells as a potential source of treatments for multiple cancers.
Characterizing novel transcripts enriched in human embryonic stem cell lines
Human embryonic stem cells were successfully cultured in a lab for the first time in 1998. Scientists believe that transplanting these cells holds great promise for treating injury and disease because they have the unique ability to replicate themselves indefinitely and develop into a wide variety of other types of cells. But a number of challenges have to be tackled before stem cells can be safely used in the treatment of patients. These include understanding and being able to control how stem cells are transformed into other types of cells, overcoming immune rejection in patients receiving transplanted cells, and understanding any links between stem cells and the origin of cancer. Jaswinder Khattra is tackling a related challenge: defining the activity of novel genes and proteins in stem cells. Although thousands of human genes are known, many remain uncharacterized. Khattra is investigating the properties of novel genes discovered in stem cells to define how they act within the cells, and whether they play a role in controlling how stem cells differentiate into other cells. This research also examines the proteins produced by these genes and how they interact in regulating cell growth and function. Improved understanding of the molecular structure and function of these genes and proteins could contribute to improvements in cell-based therapies and drug screening for a range of diseases.
Spiritual Coping in Portuguese Immigrants to British Columbia
Numerous studies on the relationship between spirituality and mental and physical health have demonstrated that spiritual coping is an effective way of dealing with stress. Most research in this area has been conducted with members of ethnic and religious majorities. But little is known about how ethnic and religious minorities employ faith in coping with stress. Derrick Klaassen is examining the spiritual coping practices of Portuguese immigrants to British Columbia. Susan James and her colleagues at the University of British Columbia demonstrated that many of these immigrants suffer from a culture specific disorder termed agonias, translated as “”the agonies””. North American health care providers have generally misdiagnosed this problem as indigestion rather than anxiety or stress, and as a result the treatments have remained ineffective. Klassen has two goals for his research. The first is to add to the understanding of effective intervention for agonias by exploring the various healing systems that Portuguese immigrants employ (e.g. mental/health systems, spiritual, community, and cultural resources). The second goal is to examine the ways in which Portuguese immigrants use spiritual strategies to cope with agonias. Klaassen’s research involves conducting focus groups and revising an existing assessment tool for this community. The resulting questionnaire will serve both practitioners and scholars in their investigations of the role of spirituality in coping with stress in Portuguese immigrants. This project is part of a multi-stage program of research that will formulate a culturally sensitive treatment manual for health providers.
Knowledge translation of health outcome measurement research into clinical practice to improve health care effectiveness and efficiency in a Prevention and Early ACtive Return-to-work Safely (PEARS) …
With population growth, an aging population, and an aging and supply-limited workforce of health professionals, British Columbia is challenged to sustain its current levels of health services in the face of unprecedented demand. In this context, the use of valid health outcome measures (OMs) is important to evaluate and improve the results of various interventions for health professionals with musculoskeletal injury (MSI)-related disabilities. Prevention and Early Active Return-to-work Safely (PEARS) is a primary (injury prevention) and secondary (physiotherapy for MSIs) program designed to reduce disability in healthcare workers who have sustained a workplace injury. Outcome measures used in the program pilot included Activity-level self-report disability questionnaires. With expansion of PEARS across BC, only Participation-level outcomes like time-loss duration and level of return-to-work were retained. Currently, few physiotherapists in PEARS are using disability measures, limiting ability to measure effectiveness of the secondary prevention component of the program. This further limits ability to improve outcomes through predictive modeling and examining effectiveness of the variety of available treatments. Allan Kozlowski is evaluating a training program intended to promote the adoption of self-report outcome measures by PEARS program physiotherapists. In addition to information about how to use the OMs, individual- and organizational-level barriers will be identified and addressed. The objective is to demonstrate that physiotherapists can measure disability outcomes as part of their practice without diminishing patient service. Implications of this work include enhanced decision-making for individual patients, identifying ‘best-practice’ treatments, managing distribution of resources within health authorities, and development of enhanced predictive modeling of outcomes, all of which would contribute to a viable and sustainable health care system.
Characterizing the role of palmitoylation in the trafficking of multispanning membrane proteins to the cell surface
Molecules are transported to various parts inside the cell to maintain vital functions, such as cell growth and communication. For example, many proteins regulate the intake of nutrients or detect external signals — it’s crucial to cell survival that these proteins are transported to the cell surface so the cells can recognize and respond appropriately to the different stimuli they encounter. However, there is much to be learned about the way these proteins are transported. This is the focus of Karen Lam’s research, in particular, understanding the mechanisms by which the saturated fatty acid palmitate attaches to proteins (I do not work with brain cells, but with yeast cells, which serve as a model) and affects their transport to the cell surface. For example, palmitate attaches to various proteins found in brain cells. Many of these proteins help chemicals called neurotransmitters send signals in the brain, a process that’s essential for learning and memory. Defects in this communication can result in neurological diseases like Alzheimer, Huntington and Parkinson’s. Lam wants to determine what causes defective function and transport in these proteins by modeling the processes in yeast cells. Understanding the fundamental mechanisms of palmitate attachment may lead to the development of molecular-based therapies to treat a variety of neurological disorders.
Assessing reward-entrainment as a means to activating and identifying the food-entrainable pacemaker
Optimal functioning requires organisms to anticipate and adapt to daily environmental changes driven by the cycle of the sun. Entrainment is the process by which daily rhythms of behaviour and physiology are synchronized to the environment. Shift-workers and air travelers are often out of sync with their environment due to a mismatch between their internal clock and the external environment. This dyssynchrony leads to general discomfort and reduced performance known as shift-work malaise or jet-lag. This has a detrimental effect on health, performance, levels of productivity and quality of life. Glenn Landry aims to achieve a better understanding of the mechanisms of entrainment. In mammals, an area of the brain called the suprachiasmatic nucleus acts as a master pacemaker. In animal models that have access to food and water without restriction, damage to this area of the brain eliminates all daily rhythms. However, if food is restricted to one to two meals at a fixed time each day, these animal models are still capable of anticipating the feeding time. This shows that a separate pacemaker exists for anticipating food. But identifying this food-entrainable pacemaker has been a challenge since many brain structures are activated during food restriction, making it difficult to isolate the pacemaker from background activity. Landry is testing a recently developed strategy to filter out this background activity. By using a number of different stimuli capable of activating the food-entrainable pacemaker, he aims to isolate this pacemaker by identifying brain areas activated in common across these stimuli. Landry hopes identifying the food-entrainable pacemaker could ultimately lead to new approaches to re-setting the clocks of shift-workers and air travelers, improving health and productivity.
The effect of reward expectation and dopamine release on the mechanism of the placebo effect in Parkinson's disease
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects about 100,000 Canadians. It occurs when cells that produce dopamine in the brain die. Without enough dopamine to send signals to the striatum, an area of the brain that controls movement, people with Parkinson’s develop tremors, stiffness and balance problems. Patients take medication to replace the missing dopamine, but this often produces troubling side effects. Interestingly, a significant placebo effect can occur in patients with Parkinson’s, with patents showing an improvement in symptoms due to their belief that a particular treatment will be beneficial. Sarah Lidstone is expanding on her earlier MSFHR-funded research to study how patients’ expectations for an improvement in symptoms actually produce measurable improvement. Using positron emission tomography (PET), a powerful brain scanning technique, Sarah has shown that patients with Parkinson’s disease release dopamine in the brain when given a placebo they thought was medication. Dopamine is also released in the same brain areas when people anticipate receiving a reward such as money or food, a response also generated in drug addiction. Sarah is examining whether the placebo mechanism in Parkinson’s taps into the same process as reward anticipation. If so, this research could lead to better treatments for the disorder. It could also inform treatment for drug addiction and other conditions influenced by a placebo effect or dopamine, including pain management, depression and obsessive-compulsive disorder.
Investigating the Role of the O-GlcNAc Post-Translational Modification in the Development of Type II Diabetes and Alzheimer's Disease
There is a growing prevalence of type 2 diabetes. It has been estimated that more than 20 million people have the disease in the United States alone. Type 2 diabetes is a disease characterized by resistance of our bodies to insulin, a hormone needed for normal metabolism of carbohydrates, fats, and proteins. This resistance leads to prolonged elevation of blood sugar levels, eventually giving rise to the diseased state. Understanding what events lead to insulin resistance is an intense topic of research. Nevertheless, the precise molecular mechanisms by which insulin resistance arises still require delineation in order to fully understand the disease Building on his MSFHR-funded Master’s research, Matthew Macauley is investigating what the role of proteins modified by a sugar known as GIcNAc have in causing insulin resistance. One hypothesis is that high levels of glucose over a long time period may increase GlcNAc modification and that this in turn results in insulin resistance. Macauley is using an enzyme inhibitor of O-GlcNAcase to artificially create elevated levels of GlcNAc in animal models to determine if insulin resistance and type 2 diabetes ensue. Using this same enzyme inhibitor, Macauley is also conducting a separate study to increase GIcNAc attached to tau, a key protein involved in the development of Alzheimer’s disease. The goal of this study is to determine if the inhibitor can prevent or delay the onset of Alzheimer’s in an animal model.
Goal adjustment processes and caregiver health: Can giving up be a good thing?
Mounting evidence indicates that caring for a family member with a chronic illness not only reduces the quality of life for the caregiver, it also increases the caregiver’s risk of becoming ill. Little is known about the specific mechanisms by which caregiving impacts health and well-being. One important factor may be the caregiver’s ability to adjust personal family and career goals to meet the demands of the difficult situation. If a caregiver is able to let go of goals set before the diagnosis, such as getting a promotion at work or building a vacation home, he or she may have an easier time adjusting to this new role, and in turn, experience reduced distress and better physical health. Teresa Marin is examining the impact of tendencies to adjust goals on both psychological and physical well-being. Once she has determined the relationship between goal adjustment and health in the context of caregiving stress, it will be possible to apply this knowledge to clinical interventions designed to foster better coping skills among caregivers. This research follows Marin’s MSFHR-funded Master’s work, in which she analyzed the mental and physical health of spouses caring for cancer patients to determine the daily impact of expressing or suppressing their emotions.