Tendon has to withstand high tensile forces to do its job properly, acting as a mechanical link between muscle and bone to allow joint movement. Repetitive-use tendon injury, known as tendinopathy, affects workers in many key Canadian industries, as well as professional and recreational athletes. Standard anti-inflammatory treatments are unsuccessful in treating tendinopathy, and new treatments are needed to relieve the burden of chronic tendon pain. Normal tendon is composed of rope-like molecules (type I collagen). In contrast, in tendinopathy the collagen can become spongey – like in cartilage (type II collagen). The tendon becomes less able to resist tensile forces, and more prone to microtearing, pain and rupture. Dr. Alexander Scott is investigating what triggers tendon cells to switch their metabolism to produce less type I collagen and more type II collagen. Scott is conducting a combination of molecular and biomechanical studies both with tendon fibroblasts and with tendon progenitor cells. Scott is also studying transcriptional regulation during tendon injury using a transgenic reporter system, and in patients with tendinopathy. Scottâs research is aimed at developing evidence-based treatments for chronically painful tendons. Ultimately, this could open up new therapeutic options for restoring tendon health.
Research Location: University of British Columbia - Point Grey
Cognitive contributions to checking compulsions
Obsessive-compulsive disorder (OCD) is an anxiety disorder that afflicts three percent of all Canadians. The disorder is characterized by intrusive and unwanted thoughts, images or impulses that cause anxiety, and that are temporarily relieved by the execution of specific compulsions. Obsessions and compulsions can occupy a large proportion of individuals’ time and energy and can interfere with daily routines, functioning at work, social activities and relationships with others. Checking compulsions are among the most common manifestations of OCD. Individuals with checking compulsions have intrusive concerns that they have failed to perform some task (such as locking the door or turning off the stove) and feel compelled to repeatedly check to ensure that the task was indeed completed. Preliminary evidence suggests that impaired prospective memory may play an important role in checking compulsions. Prospective memory is the ability to remember plans and intentions at a later moment. Everyday life and clinical observations show that checkers’ compulsions are related to this future-oriented aspect of memory and that the types of activities that tend to trigger checking compulsions are prospective memory tasks. Dr. Carrie Cuttler was previously supported by MSFHR with two research training awards. Her current work continues her exploration of whether individuals with checking compulsions have a cognitive deficit related to prospective memory. She hypothesizes that checking compulsions may develop to compensate for an impairment in prospective memory. In other words, individuals who frequently forget to perform tasks may develop a strategy of repeatedly checking to ensure that important tasks are not forgotten. Cuttlerâs research focuses on improving our understanding of the mechanisms underlying OCD. The results will improve the quality of OCD patients’ lives by setting the stage for more effective treatments for reducing the frequency of checking compulsions.
Peripheral neurophysiological basis of sensorimotor deficits in individuals with essential tremor
Essential tremor (ET) is a neurological disorder characterized by shaking of the hands (and sometimes other parts of the body) that occurs with voluntary movement. Often mistaken for Parkinsonâs disease, it is the most common tremor disorder. Approximately 75 per cent of people living with ET experience some limitation in their activities, and these limitations typically get worse with increasing age. Therapies for essential tremor focus on tremor reducing medications, but effective treatments remain limited. Consequently, new insights into disease mechanisms are needed to guide the development of more effective therapies. The origins of essential tremor are believed to involve abnormal rhythmic activity in the brain, which then travels down to the peripheral nervous system. However, the specific neural pathways that the tremor travels, as well as how ET influences the recruitment of muscles for movement, remains unclear. Also unknown is the impact of tremor on sensory receptors found within skeletal muscles, which provide the sense of position and movement of the limbs. Dr. Martin HĂ©roux is conducting studies on British Columbians with ET to determine how their muscles and sensory receptors are affected by abnormal rhythmic activities of essential tremor. He hopes these studies will increase our knowledge of the neural mechanisms involved in the generation of essential tremor and provide a better understanding of the motor-sensory deficits associated with tremor disorders. Ultimately, this knowledge could contribute to the development of more effective anti-tremor therapies.
Modulating mood with transcranial direct current stimulation: basic research and clinical applications for treating depression
Approximately 8 per cent of all Canadian adults will experience at least one major episode of depression during their lifetimes, and up to 6.5 per cent of Canadian children currently meet the criteria for clinical depression. Efforts to understand the neural mechanisms underlying depression and to develop new treatment methods for the mood disorder have the potential to facilitate improvements in quality of life for people throughout Canada and around the world. Neuroimaging studies show that negative mood and depression are associated with increased activity in the right prefrontal cortex and decreased neural activity in the left prefrontal cortex. Dr. Bradley Vines is examining how changes in neural activity in the prefrontal cortex influence mood. He is also exploring the therapeutic potential of transcranial direct current stimulation (TDCS) as a treatment for clinical depression. TDCS is a safe, painless, and non-invasive brain stimulation technique that modulates neural activity in targeted brain areas. It has been shown to significantly influence behavioural and cognitive performance. The technique involves running a low-level direct current between two electrodes placed on a person’s scalp. The neurons underneath the positively-charged anode fire more rapidly, whereas the neurons underneath the negatively-charged cathode become less active. Using tDCS, it would be possible to simultaneously increase neural activity in the left prefrontal cortex and decrease activity in the right prefrontal cortex â potentially correcting the neural imbalance that is characteristic of depression. Vinesâ research promises to advance our understanding of how the prefrontal cortex contributes to emotional states and mood disorders, and to determine the viability of using tDCS as a therapy for depression.
Defining perceptions and utilization of pharmacotherapy for menopausal symptoms among Chinese immigrant women in British Columbia
By 2017, one in five people living in Canada will belong to a visible minority group, and nearly half (between 3.2 and 4.4 million) will be Chinese or South Asian. A variety of factors â including language, education, socioeconomic status and employment â affect health and access to health care. Gender, ethnicity, and immigration are also increasingly recognized to have a significant impact. Medication use for menopausal symptoms has not been explored in the context of gender, ethnicity and immigration in Canada. Women, particularly Chinese women, have historically been underrepresented in clinical trials, resulting in a limited understanding in this group. As a result, few studies have examined Chinese immigrant womenâs experiences with medications for menopausal symptoms. Dr. Elaine Chong will focus on a knowledge gap relating to medications used for menopausal symptoms, among Chinese immigrant women who access health services through a specialized outpatient clinic in Vancouver. Chinese immigrant women constitute a group that has health disparities and may have less access to evidence-based care than other women in Canada. Chongâs research will help shed light on differences in medication use and health disparities among a vulnerable group. She hopes these results can be applied to culturally-appropriate interventions that support Chinese immigrant women in attaining optimal health status.
Healthy child development: A multidimensional evaluation of parenting in the context of neighbourhood
Early childhood development (ECD) is a determinant of health and well-being across the lifespan. Recent results show that children’s developmental readiness at school is generally predicted by the socio-economic characteristics of the neighbourhoods in which they live. However, findings also reveal ‘atypical’ neighbourhoods, where neighbourhood socio-economic characteristics appear to have less influence on children’s development. One possibility in understanding these inconsistent findings points to familial and parenting influences on children’s health and development. Among families, parenting is a key factor in the protection, nurturing, and socialization of children, with important implications for developmental health. Parenting may also serve as an indirect pathway through which neighbourhood factors operate on young children’s health and development. Parents have a primary role in either transmitting or buffering neighbourhood influence on children’s development, especially during early childhood when children have quite limited direct exposure to the neighbourhood. Dr. Anat Zaidman-Zait is developing a multidimensional measure of parent-child interactions and will examine parenting in the context of the neighbourhood environment. Specifically, she will study parents of preschoolers from diverse neighbourhoods across BC, collecting information on parenting, neighbourhood socio-economic characteristics, parents’ perceptions of their neighbourhood, family demographic characteristics, and family and parents’ psychosocial functioning. Zaidman-Zaitâs research promises to highlight processes through which families who are exposed to different conditions remain resilient and are able to successfully support the healthy early development of their children.
Organizational effects of the neonatal testosterone surge on the hypothalamic-pituitary-adrenal axis
Mood disorders affect nearly 10 per cent of the population globally and have an enormous impact on society as a whole. Stress, and how the body deals with it, is known to be a contributing factor in mood disorders. One of the main neural systems involved in stress is the hypothalamic-pituitary-adrenal (HPA) axis, a complex system that connects input from the brain to the synthesis and release of glucocorticoid hormones from the adrenal gland. Although glucocorticoids (e.g. cortisol) play an important short-term role in helping us respond to stress, prolonged activation of the HPA axis can detrimentally affect brain function and behaviour. Research indicates that sex steroids such as testosterone help shape stress-related pathways in the brain, and contribute to why some individuals are predisposed to stress-related mood disorders. Prior to birth, males normally experience a surge in testosterone that has been shown to have a profound and permanent influence on brain structure, behaviour, and HPA function during adulthood. However, where and how this occurs in the brain has not been determined. Brenda Bingham is determining the HPA-regulating regions in the brain that are altered by this early surge in testosterone. She will explore how early testosterone exposure determines the capacity of these brain regions to respond to changes in circulating testosterone levels during adulthood. She is focusing on the function of androgen receptors, which allow the brain to respond to testosterone, and on the neuropeptide vasopressin. Binghamâs research will provide insight into the HPA-regulating brain regions and circuits that are altered by testosterone exposure early in life. Ultimately, she hopes this work will lead to the development of novel therapeutic strategies aimed at tackling depressive disorders.
Functional significance of adult hippocampal neurogenesis
The hippocampus is critically important for learning and memory and is one of only two brain regions than can produce new neurons in adulthood. There is some evidence that the addition of new neurons (neurogenesis) in the hippocampus is involved in or may even be required for the normal functions of this region. The rate of neurogenesis declines with age. It is widely accepted that aging is also associated with a decrease in memory performance, especially on the types of tasks that require the hippocampus. Decreased neurogenesis has been proposed as one possible factor that may reduce the efficiency of hippocampus-mediated learning and memory. And while there is believed to be a relationship between hippocampus-dependent learning and cell proliferation and survival, itâs not known What exactly this relationship is: whether neuronal growth affects hippocampus-dependent learning, or whether hippocampus-dependent learning affects the rate of neurogenesis. Other studies also suggest there may be a critical cellular age for new neurons when their survival can be altered. However, given the many conflicting studies in the literature, it is unlikely that there is a simple relationship between level of neurogenesis and memory performance. Jonathan Epp is exploring these various factors to determine the processes by which hippocampal neurogenesis occurs in adulthood, and the importance of neurogenesis to learning and memory. Using animal models, he will clarify whether cell survival can be enhanced at all times or whether there is a critical cellular age during which survival altering factors may have an impact. Epp hopes that by developing a better understanding of these relationships in the brain, this knowledge could be applied to generating therapeutic strategies for dealing with memory loss associated with aging, dementia and brain injury
ZIP-5/Bach1 antagonizes SKN-1/Nrf2 in development and longevity
Many of the genes involved in aging are also involved in embryonic development. These same genes have been linked to cancer development (carcinogenesis). An example of such a gene is daf-2, which is the worm version of the human insulin and insulin-like growth factor receptor. When this gene is mutated in worms (C. elegans), they live twice as long. Victor Jensen studies genes regulated by daf-2 in order to find new genes implicated in longevity. He has identified a gene called zip-5 that, when mutated, allows worms to live 25-35 per cent longer and remain healthier. zip-5âs ability to extend longevity depends on the function of another gene called skn-1. SKN-1 has several functions: it contributes to embryonic gut development, it regulates stress response and is implicated in increased longevity that results from dietary restriction. The human counterpart to SKN-1 is called Nrf2, which regulates stress resistance in human cell lines. Nrf2 also provides a chemoprotective effect against carcinogenesis, injury and inflammation. The action of Nrf2 is opposed by a gene called Bach1 â the human counterpart of the worm zip-5 gene. Inhibiting Bach1 allows for easier activation of Nrf2 target genes, resulting in a stronger chemoprotective effect in cancer. Jensenâs research genetically characterizes this antagonistic relationship and identifies the novel role of zip-5 in longevity and development. He is working to determine whether the Bach1/Nrf2 relationship is parallel to the zip-5/skn-1 relationship in C. elegans, and whether it explains zip-5âs effect on longevity. He hopes his research will reveal a new role for zip- 5/Bach1 in development and longevity, and open the door to new studies looking at how Bach1 inhibition affects carcinogenesis and aging.
Somatic and gametic loss of imprinting (LOI) in mammalian development: studies using a novel imprinted transgene on the mouse distal chromosome 7 (MMU7) imprinted region
Genetic inheritance primarily results from the interplay of dominant and recessive genes between two parents. With certain genes, however, gene expression is parent-of-origin-specific: these genes will always be expressed from either the maternal or paternal chromosome. This process is known as genomic imprinting, which creates a mark, or âimprintâ, on the chromosome. Gametes are reproductive cells, such as sperm or eggs, which contain a single set of chromosomes. During their maturation, their imprints are erased then re-established. Between the erasure and re-establishment phases is a transitional loss of imprinting (LOI) state. Problems with the erasure or re-establishment of imprints in gametes can result in a number of human genetic disorders, including Prader-Willi, Angelmann, Silever-Russell, and Beckwith-Wiedemann Syndromes. In non-gamete tissues, on the other hand, imprints are generally thought to be maintained throughout life and LOI is often considered to be an abnormal condition. Both loss of epigenetic marks and loss of parent-specific gene expression are observed frequently in many types of cancers, but whether this is a cause or an effect of this abnormal growth is unclear. Meaghan Jones was previously supported by MSFHR for her early PhD studies in genomic imprinting. She is now working to determine more about what causes LOI events in both gametic and non-gametic tissues. She is using a model of Beckwith-Wiedemann Syndrome to determine when LOI occurs in cells, with the hope of pinpointing factors that can cause LOI. An understanding of normal LOI in development could help alleviate the risk of imprinting defects, and could improve effectiveness of medical technologies including assisted reproductive technologies, stem cells, nuclear transfer, and cloning.