Transcriptional regulation of genes in health and disease

The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.

Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.

Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.

The medical management of human intersex: An evaluation of parent-clinician communication about treatment options

The surgical and hormonal management of intersexed children is a much more common component of pediatric care in Canada than many people realize. Intersex conditions, where noticeably atypical genitalia is deemed to require intervention, occurs in about 1:2000 live births. In the international context, driven by an increasingly well-organized coalition of intersexed people, the potentially harmful effects of these medical interventions are being debated. Proponents of standard treatment protocols justify genital surgeries with an in-the-best-interest-of-the-child rationale, claiming that to leave a child’s body in a state of sex ambiguity would inevitably lead to psychological harm and sexual maladjustment. Yet, no long-term follow up studies have been conducted to substantiate this claim. The delivery of current medical services is not structured in ways that allow for follow-up with intersexed adults, and much of the evidence from intersexed people themselves suggests that, in the long-term, the best interests of intersexed children are not protected. Many grow into adulthood feeling stigmatized and traumatized, and are left in both physiological and psychological pain by their years of medical treatment. Rodney Hunt is conducting a detailed qualitative study of parent-clinician communication to gain insight into the ways in which the current medical management of intersexed children is taken up or contested in a clinical setting. He aims to achieve a deeper understanding of the institutional and social factors that influence parent-clinician communication and decision-making when treatment options are discussed. Ultimately, Rodney’s goal is to advance current theoretical understandings of sex and gender in medicine and health policy frameworks, and to provide a valuable evidentiary base for diverse stakeholders, including clinicians, social scientists, health policy makers, intersex support groups, women’s health advocates, and those most directly affected, intersexed people and their families.

Disentangling Relationships Between Mental Illness and Youth Violence

According to Statistics Canada, Canadian adolescents are more likely than any other age group to commit violent crimes. This violence has enormous costs, including the suffering of victims, the fears experienced within a community and financial costs to taxpayers. A significant effect is the reduced opportunity for these youth who commit violent crimes. Researchers have recently identified mental illness as a possible contributing factor for youth violence. While most teenagers with mental illness are not violent, rates of violence appear higher in this group. Currently, researchers do not have a clear understanding of which mental illnesses increase youths’ risk and why. Dr. Jodi Viljoen will advance this understanding by providing health professionals and society in general with information about key relationships between youth violence and specific mental illnesses. Viljoen will interview 200 adolescent offenders in the community. The youths’ mental health symptoms, social context (e.g., peers), protective factors (e.g., supportive relationships with adults), and violent behaviour will be assessed regularly for a one-year period based on the following: structured interviews with youth and their caretakers, clinician rating scales, self-reporting questionnaires, and justice and mental health records. Her analyses will carefully examine the role of youths’ strengths and social context in predicting violence, as well as possible gender and ethnic differences in links between mental illness and youth violence. By identifying core risk factors and treatment needs in adolescent offenders with mental health issues, her research will help inform the development of effective strategies to prevent and treat violent behaviour in this critical age group, and will also advance BC as a premier centre in youth violence research and training.

Elucidating the function of Bardet-Biedl Syndrome (BBS) proteins in Intraflagellar Transport (IFT)

Cilia are fine, hairlike projections that protrude from most cells of the human body. Many of these cilia perform sensory roles such as detecting light, sensing temperature and perceiving smell. Dysfunction of cilia is implicated in a number of conditions, most notably polycystic kidney disease. The less common Bardet-Biedl Syndrome (BBS) reflects the effects of complete loss of cilia function throughout the body. Patients with this condition suffer from obesity, polydactyly (more than 20 fingers/toes), cystic kidneys, infertility and many other conditions. Analysis of cilia structures in a tiny worm called nematode Caenorhabditis elegans has provided tremendous insight into the function of BBS proteins. Research has revealed that BBS proteins are involved in the process of intraflagellar transport (IFT), the dynamic mechanism through which cilia are built and maintained. An absence of BBS proteins appears to impair cilia function, apparently by causing the IFT machinery to split apart, although other deficiencies are highly likely. Peter Inglis has developed a new approach in studying the interaction of BBS proteins within the IFT complex, focusing on how BBS proteins are involved in the rearrangement of core IFT proteins. He will dissect BBS function and assemble a general model for the role of BBS proteins in IFT. Ultimately, his work promises to shed significant light on a cellular mechanism implicated in a wide variety of human disorders.

The genetic basis of neuronal differentiation and neuronal circuit formation

Diseases or injuries affecting the brain frequently have devastating consequences for affected individuals. Despite progress in the last decade, many aspects of brain disease and brain development are still not understood with enough detail to develop effective diagnosis and treatment of disease and injury. Connectivity disorders result from defects in the formation of particular neuronal circuits that interfere with normal communication between neurons. They are especially challenging because they are often inherited and are influenced by more than one gene making it even more difficult to trace the underlying defects. It is suspected that connectivity defects are implicated in a variety of disorders including autism, schizophrenia, attention deficit hyperactivity disorder, obsessive–compulsive disorder and certain forms of epilepsy. In most cases, the nature of the circuitry defects is not understood. Dr. Hutter’s research is directed at identifying and describing central aspects of brain development, in particular how the formation of neuronal circuits is controlled and regulated at the molecular level. His research model is the simple invertebrate organism, C. elegans, which has many of the developmental control genes found in humans. By exploring the molecular basis of neuronal circuit formation in a simpler model organism, his work will contribute to a more detailed picture of the more complex circuitry of humans, and potentially to an improved ability to design drugs and other methods of treating connectivity 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.

Developing a Decision-Support Framework for Locating Regional Palliative Care Hubs in Rural and Remote Canada

Canada’s aging population is on the rise, resulting in greater demand for palliative care services (PCS). However, service delivery is unable to meet demand, particularly in rural and remote areas due to the absence of existing infrastructure, qualified medical practitioners, funding, and user volume. In addition, many of these services have been developed in urban centres, resulting in a centralization of palliative care services and facilities.

One solution to address the need to provide PCS to residents of rural and remote areas is to relocate care recipients to service-rich urban centres. However, research has documented that most Canadians prefer to spend their last days at home. The development of regional palliative care hubs is an innovative solution for delivering PCS to residents within these rural and remote communities.

Using a mixed-method study design that combines geographic information science (GIS) and spatial analysis with qualitative methods, Dr. Nadine Schuurman will determine which rural and remote BC communities are potential candidates for regional palliative care hubs, and what potential barriers exist for accessing these services — both by patients and by providers. Her research will also include the development of a GIS-based decision support tool for determining the most suitable communities for serving regional centers, and identifying the types of patients and providers most likely to benefit from having a hub in these locations.

Dr. Schuurman’s goal is to provide insight into how to provide palliative care to an aging population in rural and remote Canada and to help inform policy and program decision-making related to the allocation of health care resources.

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.

The role of O-Glycosylation in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the loss of motor neurons (specialized nerve cells) in the spinal cord, brain, and descending motor tracts. ALS leads to muscle weakness and paralysis, and is often fatal. Numerous biochemical processes have been linked to the progression of ALS, including increased levels of protein modification (phosphate units). Xiaoyang Shan is researching the role of modified sugar units, known as O-GlcNAc, in maintaining the proper functioning of neurofilaments (structural proteins) that give neurons support and shape but become damaged in ALS patients. He is also investigating the role of O-GlcNAc in maintaining healthy motor function. The findings could help increase understanding of the causes of ALS, and contribute to development of a potential treatment to slow or halt the progression of the disease.

Negotiating International Health Policy on a Local Level: HIV Positive Women and their Experiences with Infant Feeding in Vancouver, Canada

Medical research currently debates what infant feeding method should be recommended to HIV positive mothers. Studies indicate that antiretroviral treatment effectively reduces transmission of HIV through breast milk by approximately at least two-thirds by lowering the amount of HIV in the blood. However, Canadian health policy strongly discourages breastfeeding regardless of a woman’s HIV viral status after giving birth, and encourages formula feeding as the alternative. Avoiding breastfeeding may eliminate the risk of HIV transmission, but is “replacement feeding” with formula the safest most viable option? Francoise Guigné is interviewing physicians, health care providers, and educators, and women living with HIV in Saskatoon, a city reknown for breastfeeding promotion, about their recommendations and experiences with formula feeding. Preparing formula can be expensive and complicated. Guigné is assessing the social, cultural, economic and emotional challenges HIV-positive women face with replacement feeding, and, the international flows of health knowledge that doctors, health care providers and educators use to address these challenges. Compared to breastfed babies, formula fed infants suffer higher rates of diarrhea, respiratory, ear and other ailments. HIV-positive mothers must weigh these health risks against the risk of acquiring HIV through breastfeeding. Guigné’s research aims to identify and address any gaps in support services for HIV-positive mothers by improving the support networks, medical resources and counselling services currently available to them.