Intimate partner violence, which includes psychological, physical and sexual abuse, is a serious social and public health issue. The problem is particularly critical in British Columbia, which consistently has one of the highest rates of abuse of women in Canada. A woman’s risk of partner violence increases during pregnancy, and is associated with increased chance of miscarriage, premature labour, and low birth weight, as well as posttraumatic stress disorder and depression. Health care providers ask all pregnant women about violence as a routine part of their health history. However, a major barrier for caregivers is their lack of knowledge about what action to take after a woman discloses abuse. Little research has been done to determine what steps can be taken to successfully stop the abuse. Dr. Sarah Desmarais is evaluating the effectiveness of a targeted intervention, delivered in the context of primary care, to reduce violence and improve health. She will follow pregnant women – receiving care in a Lower Mainland hospital – who indicate that they have experienced partner violence. The intervention program will be provided by community health nurses and will consist of a variety of information, referral, and resource services (e.g., providing women with telephone numbers for community agencies and assisting women in contacting a women’s shelter and negotiating admission). Following the initial intervention, Desmarais will track pregnancy complications and newborn health. She will also interview women post partum about their health, their intervention experiences, and the incidence of partner violence. This research will inform the development and delivery of partner violence intervention in primary care settings, with an ultimate goal of reducing partner violence and improving women’s and newborn health.
Program: Trainee
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-Zait’s 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.
Microglia homeostasis and function in CNS disease
Microglia play a critical role as immune cells in the central nervous system (CNS), helping protect the nervous system in response to neural damage or inflammation. Microglia are also thought to play a role in neurodegenerative disorders such as Alzheimer’s disease, dementia, multiple sclerosis and amyotrophic lateral sclerosis (ALS). Microgliosis – the accumulation of microglia – is a common response to multiple types of damage within the CNS. However, the origin of microglia involved in this phenomenon remains elusive. It has been shown that, as a result of radiation therapy or bone marrow transplant, this increase may be due to recruitment of bone marrow-derived progenitor cells that are capable of forming microglia. In the absence of therapies that manipulate the body’s blood production system, however, this is not the case. Bahareh Ajami has observed in her previous studies that recruitment does not account for the massive increase in microglial cells that occur in two different CNS disease models: neurodegeneration and traumatic injury. Instead, microgliosis is solely the result of the expansion (division and growth) of microglia already residing in the CNS. She is now working to determine whether bone marrow-derived progenitor cells have a role in microglia accumulation in multiple sclerosis, which is an autoimmune disease of CNS. In parallel, she will also explore the effect of microglial cells on nerve cell survival in the CNS. Ajami’s results will not only contribute to the field of neuroscience, but could also provide new targets for developing gene and drug delivery systems that treat CNS disease.
Yeast oxysterol binding proteins and the cholesterol dependent regulation of Rho-GTPase mediated polarized cell growth
Heart disease is the leading cause of death for Canadians. More than one million Canadians currently live with this chronic disease and every year, more than 81,000 die. A major contributor to heart disease is cholesterol. Ironically, even though too much cholesterol is bad for our health, it cannot be completely removed from our bodies because it is essential for human life. Controlling dietary cholesterol is not always enough to reduce cholesterol levels in the body since our cells can also produce their own cholesterol. Loss of cholesterol regulation in our bodies not only leads to heart disease, it is also causes problems inside cells that can lead to other disease states. In fact, recent studies showed that the use of cholesterol-reducing drugs not only lowered cholesterol, they also decreased the incidence of breast cancer in Canadian women by 74 per cent. Recently, a group of cholesterol-binding proteins were identified and have been shown to mediate many of the functions linked to cholesterol. Gabriel Alfaro is using microscopy, biochemistry, and genetics to determine the mechanisms underlying how these proteins affect cholesterol regulation and mediate cellular functions. His research uses baker’s yeast as a model system, since the regulation of cholesterol in yeast is similar to its regulation in humans. Gabriel Alfaro’s research will enhance our understanding of the role cholesterol plays in the cell, and potentially point to new drug targets that could have fewer side effects relative to the current broad spectrum cholesterol inhibitors. Furthermore, his research will help elucidate the mechanism underlying cholesterol-related diseases
YB-1 induction of PIK3CA mediates herceptin resistance in Breast Cancer patients
Breast cancer accounts for more than 30 per cent of all new cancer cases in Canada. One in nine women will be diagnosed with breast cancer in their lifetime, while one in 27 will die of the disease. This translates to 23,000 new diagnoses and 5,300 deaths in Canada every year. An aggressive form of breast cancer is called the Her-2 subtype. These tumours produce a protein called Her-2, which helps the cells grow uncontrollably. The drug Herceptin acts against the Her-2 protein. While this drug is effective, there are limitations to Herceptin’s usefulness since many patients develop resistance to the drug. Recent research has uncovered a protein called Y-box binding protein-1 (YB-1), which is expressed (produced) at high levels in the Her-2 subtype of breast cancer. While the YB-1 protein is not found in normal cells, it is found in 66.4 per cent of Her-2 subtype breast cancers. This makes YB-1 an attractive target for treatment, as inhibiting it will not affect normal cells. The protein promotes tumour growth by altering the levels of other tumour-enhancing proteins, such as PI3K. Arezoo Astanehe is investigating whether the increase in PI3K by YB-1 is one reason that cells become resistant to the effects of Herceptin. She hypothesizes that by inhibiting YB-1 and PI3K expression, Her-2 cancer cells would remain sensitive to Herceptin. Astanehe’s findings could identify new drug targets to help prevent Herceptin resistance and increase long-term survival of women with this aggressive and deadly form of breast cancer.
Regulation of intestinal homeostasis by colonic goblet cells in response to commensal and pathogenic bacteria
The gut lumen (interior space of the intestine) has developed to live in harmony with trillions of bacteria, many of which are beneficial to human health by helping in digestion and making vitamins. However, this harmony can be broken if the bacteria start to enter body tissues instead of staying in the lumenal space. Preventing this is the lining of the gut surface, which is made up of a single layer of different cells, including goblet cells. Goblet cells are single-celled mucus factories, specialized to make molecules that form a layer of mucus over the intestinal wall. While the mucus layer is believed to have a protective role, its function is not well studied in people. However, animal models that that lack mucus in the gut develop unwanted inflammatory responses and even cancer, suggesting an important function for this layer. Furthermore, defective mucus production is seen in patients with inflammatory bowel disease (IBD), which is characterized by excessive immune responses to our normally friendly bacteria. Previously funded by an MSFHR Junior Graduate Studentship award, Kirk Bergstrom is continuing his studies on how mucus-producing goblet cells promote healthy interactions with beneficial bacteria in the gut, and how they defend against harmful bacteria. He is using animal models of bacterial-driven gut inflammation, including an infection model that copies human disease. Bergstrom’s studies will shed light on how goblet cells help maintain this delicate balance within the gut. Also, since mucus production by goblet cells can be controlled by certain foods, these studies could lead the way toward new, noninvasive therapies based on nutrition to treat patients suffering from bacterial infections of the gut, or IBD.
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. Bingham’s 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.
Extraction and evaluation of transcription factor gene-disease association
Genes are the basic blueprints used by the cells in our body. When a gene is modified, the cells in our body can be affected; in the worst case, this can cause a disease. A researcher can often be faced with several candidate genes to study in relation to a particular disease, and choosing the genes with the best potential for discovery is important for making the best use of research resources. Around the world, researchers are studying thousands of different genes to understand their roles in health and disease states. Their findings – in the form of abstracts and annotations – are captured in a variety of databases. However, this vast source of biomedical literature is an under-utilized resource. Powerful computational biology methods are required to allow researchers to mine this information. Warren Cheung is developing an automated system that can examine the available biomedical literature and quantitatively determine which genes are most likely involved in a particular disease. Not only will the system identify previous relevant findings, its integration of data and annotations from many studies is expected to identify previously unknown associations between genes and diseases. Cheung’s research will initially focus on the involvement of transcription factor genes in brain diseases and cancer. However, the techniques developed and tested will be easily adaptable to all types of genes and diseases. Cheung’s award is jointly funded by MSFHR and the Down Syndrome Research Foundation. With the ability to automatically look at all the papers that have been published on genes and their functions, this system will make unbiased predictions and previously unknown linkages. This promises to be a powerful tool for understanding genes and disease.
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, it’s 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
The development and application of algorithms for interpreting next-generation Solexa sequencing data: creation of a genome-wide breast cancer mutation map
Breast cancer is the most common malignancy in North American women, with more than 20,000 new cases diagnosed each year in Canada. Promising new treatments like Herceptin take advantage of genetic changes that occur in breast cancer cells, which can be detected by assessing specific tumour biomarkers. This approach is possible thanks to the successful sequencing of the human genome and the development of faster, cheaper sequencing technologies. One such technology is the Illumina 1G, a sequencing platform that can sequence a full genome for medical purposes in a matter of weeks. However, this new technology requires the development of new methods for the analysis and interpretation of the output. Anthony Fejes is demonstrating the utility of these new sequencing technologies by applying them to the study of breast cancer. By fully sequencing the genome of breast cancer-derived cell lines, he will create a genetic “map” that identifies the location and nature of the changes underlying the transformation of healthy cells into cancer cells. He will then validate the maps by identifying specific genetic errors that contribute to the development of cancer, and attempt to identify currently available drugs that can be re-purposed to target these broken cellular elements. This combination of sequencing, computational analysis, and drug candidate testing provides a single “”genome-to-therapeutic”” work flow, demonstrating a method that can be applied to the development of personalized medicines. Fejes’ research will also allow researchers to find new approaches to the treatment of cancers, through development of a technique that can be applied to other genetic disorders.