OCD translational multi-modal research program

According to the World Health Organization, obsessive-compulsive disorder (OCD) is one of the top 10 causes of disability. The disorder often begins in childhood and interferes with normal development. This disabling mental illness affects approximately 2 – 3 percent of British Columbians and, although treatable, is often under diagnosed.

The aim of Dr. S. Evelyn Stewart's research program is to improve the lives of BC children and families living with OCD. Her goal is to improve the evaluation and awareness of pediatric OCD in BC by conducting research to guide scientific and clinical understanding of OCD and its management by health professionals, and by establishing national and international linkages, which will lead to future research collaborations. Dr. Stewart's specific objectives for the first five years are to 1) create a unique research program within the new pediatric OCD clinic at BC Children's Hospital that is closely tied with the community, 2) establish a pediatric OCD DNA and research data site for BC, 3) launch a comprehensive patient-assessment method, and 4) investigate the outcomes and effectiveness of the program itself.

This program is unique, as it pulls together expertise from the clinic, the community and the laboratory. One important feature of Dr. Stewart's program is the effective transfer of new information between the clinic and the research lab in order to help the outcomes of practice inform research. Dr. Stewart anticipates this program will help limit the suffering and health-care costs related to OCD. The program is anticipated to develop into the first North American OCD Centre of Excellence.

Childhood lung diseases: Infectious and inflammatory mechanisms

Lungs are for life. Unfortunately, the most frequent long-term illnesses in children and babies are respiratory system conditions. Children's lungs can be damaged in many ways: bacterial and viral infections, asthma, or faulty genes causing thick mucus to accumulate in the lungs of children with cystic fibrosis. Even the oxygen and artificial ventilation needed to sustain the lives of premature babies can cause lasting lung damage. A feature shared by all these serious childhood lung diseases is that some of the damage is caused by activation of the innate immune system, which is an important part of our immune defense network. The innate immune system is like a “double-edged” sword. While innate immunity is essential for keeping us healthy, it can cause excessive lung-damaging inflammation if the activity is not carefully controlled.

To prevent lung damage, Dr. Stuart Turvey is examining the systems that control the activity of the innate immune system. These control elements are known as negative regulators. His team will study these negative regulators in a variety of childhood lung diseases spanning premature babies and lung infections through to asthma and cystic fibrosis. The unique aspect of this project, and of Dr. Turvey's group in general, is a commitment to translational research focused on people with lung disease. This means research results from the lab bench are applied directly to patient care.

Rather than relying exclusively on laboratory (animal or cell) models of disease, Dr. Turvey’s team plans to examine genetic material donated by people affected by infectious and inflammatory lung diseases. The results of this work will be an exciting starting point for gaining a better understanding of the causes of childhood lung diseases and developing new medicines to safely control the damaging inflammation that occurs in the lungs of so many babies and children.

Relationship of Neonatal Pain and Early Brain Development of Preterm Infants on Motor Outcomes at 18 months

Between 2005 and 2009, more than 16,000 infants in British Columbia were born prematurely. Prematurely born infants are at increased risk for developing motor problems that, in many cases, significantly interfere with daily life and school performance. This degree of motor difficulty is often referred to as developmental coordination disorder, or DCD. Children with DCD struggle with many typical tasks, such as tying shoes, riding a bike, handwriting or participating in sports. While it was once believed that children with DCD would outgrow their motor difficulties, studies have shown that these difficulties can persist into adolescence and adulthood. In addition to physical concerns, children with DCD experience other issues, including difficulty with social and peer relationships, lower self-worth and self-esteem, anxiety and depression, and other emotional health concerns. Thus, there is an urgent need to develop rehabilitative therapies to prevent these lifelong complications.

Dr. Jill Zwicker's research program focuses on understanding how the process of early brain development influences motor-skill development. Previous work suggests that DCD may be caused by abnormal brain development, but this has yet to be confirmed. Dr. Zwicker, an occupational therapist with a clinical and research interest in DCD, is using different brain-imaging techniques and is collecting information about health and treatments from a group of 175 premature infants. The babies will have a brain scan in the first few weeks after birth and will have a second scan around the time they would have been born, had they made it to full term. Measurement will be used to compare brain development between these two points in time.

Dr. Zwicker suspects there may be a relationship between brain development and exposure to pain, and that these factors may affect motor development, so she will also gather information about the number of skin-breaking procedures (for example, needle pokes) that the infants receive. In addition, her research team will collect information about other factors that may influence brain and motor development, including medications received, days on oxygen, illness severity, infection, and lung disease.

By having a stronger understanding of the factors that contribute to the development of DCD in children born prematurely, Dr. Zwicker hopes her research will help prevent poor motor outcomes and help develop new therapies to improve motor and functional outcomes for children born prematurely.

The role of ABCA1 and microRNAs in the regulation of beta cell function

Type 2 diabetes currently affects 2.5 million Canadians. Elevated blood cholesterol levels increase the risk of developing diabetes. Scientists are starting to understand the molecular basis of diabetes and have recently discovered that a deficiency of the ABCA1 molecule, a transporter that removes cholesterol from cells, leads to the accumulation of cholesterol in the insulin secreting-beta cells in the pancreas. This cholesterol accumulation leads to impaired insulin secretion and contributes to diabetes. Therefore, influencing the levels of ABCA1 molecules in beta cells may help control both cholesterol and diabetes. The objective of Dr. Nadeeja Wijesekra’s research is to discover new ways to regulate ABCA1 levels in beta cells in order to improve beta cell function and survival. Her project involves the use of small molecules called microRNAs to regulate ABCA1 levels in mouse beta cells. She will identify specific microRNAs that regulate ABCA1 levels in beta cells and determine how they influences beta cell function by measuring insulin secretion and changes in cholesterol levels. Furthermore, these microRNAs will be used in diabetic mouse models to assess whether their disease condition can be improved. Since increased ABCA1 has been shown to have a positive impact on beta cell function, finding ways to increase ABCA1 levels in these cells may be helpful in ameliorating beta cell defects present in diabetes. Thus these studies are the first to outline a therapeutic strategy to modulate cholesterol in beta cells in order to improve whole body glucose homeostasis.

The role of IL-17 in the pathogenesis of type-1 diabetes

Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease that usually presents in children and young adults. In patients with Type 1 diabetes, the body attacks itself, thus destroying insulin-producing cells in the pancreas that regulate blood sugar (glucose). A diagnosis of Type 1 diabetes currently translates to a lifetime burden of insulin injections and a risk of multiple complications for children in Canada. T-cells are white blood cells and play a key role in the immune system to control infection. In healthy individuals, a type of T-cell, called Th17, provides a strong defense by guiding the immune system to attack bacteria and virus-infected targets within our bodies. A recent discovery of elevated numbers of Th17 cells in children newly diagnosed with Type 1 diabetes suggests that these cells may play a key role in the early development of this disease in young patients. Interestingly, Th17 cells have been associated with other autoimmune diseases, such as Crohn’s disease and multiple sclerosis. Dr. Ashish Marwaha is working to identify novel treatments for Type 1 diabetes by understanding the function of Th17 cells in the course of a child developing Type 1 diabetes. To understand if there is a specific genetic mutation that can predict which children will have high levels of Th17 cells and therefore at risk of developing Type 1 diabetes, he will be analyzing stored blood samples from British Columbian children with this disease. The findings from this study will determine the extent to which Th17 cells are harmful in Type 1 diabetes and may open the door to new treatments for childhood diabetes that target Th17 cells.

Mortality in children under five years of age in Uganda following hospitalization for sepsis: A prospective cohort study

The United Nations Millennium Development Goal number four commits to reducing child mortality by two thirds before 2015. However, worldwide, eight million children under the age of five die annually. The majority of these deaths occur in resource-poor countries and are a result of a condition called sepsis. Sepsis usually occurs following severe infections, when the body’s immune defences begin to cause harm, leading to death if left untreated. Most infectious diseases including pneumonia, diarrheal diseases and malaria, when severe, result in sepsis. Studies from Kenya have shown that among children admitted to hospital with a severe infection, more children die within the two-month period after leaving the hospital than during their hospital stay. While there are a number of studies regarding hospital treatment, no studies have been conducted to investigate predictors of death after leaving the hospital. Knowledge of these predictors can help to identify which children are in the high- and low-risk groups and thus enabling closer monitoring of high-risk children following discharge. These risk predictors can also be used in clinical trial design so that treatments can be developed, tested, and eventually implemented to reduce sepsis-related deaths following hospitalization. The goal of Dr. Matthew Wiens’ research is to identify predictors of child death from sepsis after leaving the hospital. To do this, he will study a group of children under the age of five who were hospitalized for sepsis at two hospitals in the Mbarara district of Uganda (the Mbarara University Hospital and the Holy Innocents Children’s Hospital). During the hospitalization phase he will collect information on a series of characteristics such as the type and severity of infection, nutritional status, maternal education, access to clean water and many other potential predictors. During the six month follow-up phase after hospitalization the health outcomes of these children will be determined. Using these predictors, Dr. Wiens along with his supervisor and team of researchers will create a scoring system that allows doctors to identify children who at high and low risk of death after discharge and intervene accordingly. Understanding the factors that are likely to influence a child’s long-term health outcome after leaving the hospital will help in the development and implementation of effective interventions to reduce childhood mortality in the developing world.

Allele-specific silencing of the mutant huntingtin gene in a mouse model of Huntington disease

Huntington disease is a fatal and inherited neurodegenerative disease. It is characterized by diminished voluntary motor control, cognitive decline and psychiatric disturbance. Symptoms of the disease first appear in the thirties to fifites, with death usually occurring 15 to 20 years later. While there are still no effective therapies for this disease, recent research discoveries have provided insight into how the disease develops. The normal huntingtin gene encodes a protein that is important for neuronal health. Although everyone has two copies of the huntingtin gene, people with Huntington disease have one normal copy and one mutated copy. When a person has a mutated version the gene, the huntingtin protein accumulates within cells and engages in a variety of aberrant interactions that cause disease symptoms.

Dr. Amber Southwell is working to develop a strategy for turning off the mutant copy of a patient's huntingtin gene in order to prevent or delay the onset of the disease. Her lab has identified genetic characteristics that are more common in mutant than in normal huntingtin genes and have generated therapeutic reagents that specifically target these mutant variations. This effectively switches off the mutant but not the normal gene in cellular models of Huntington disease and results in the selective reduction of the mutant huntingtin protein.

Dr. Southwell will test the efficacy of these candidate therapeutics by measuring their ability to reduce the level of the mutant but not the normal protein in the living brains of a mouse model of Huntington disease. She will also evaluate how the therapeutic reagents influence the behavior and brain pathology of these mice. This targeted approach of selectively silencing the mutant gene while sparing the normal gene is preferable to other approaches that prevent the expression of any huntingtin protein. The normal huntingtin protein is important for neuronal health, and long-term reduction of this protein may not be well tolerated. Hopefully this targeted approach will lead to new therapies to prevent or delay Huntington disease onset.

Mechanisms underlying protective effects of HDL and ABCA1 in beta cell survival

Diabetes is a major cause of disease and death in BC. According to a report from the Canadian Diabetes Association, 7 percent of BC residents currently have a diagnosis of diabetes, and this number is expected to rise to more than 10 percent by 2020, by which time diabetes-associated heath care costs in BC are expected to rise to $1.9 billion per year. Diabetes and cardiovascular disease are intimately related, and having one of these diseases is a strong risk factor for the other. Altered blood cholesterol levels increase the risk of developing both cardiovascular disease and diabetes. Blood cholesterol is carried in two types of particles: low density lipoprotein (LDL) particles and high density lipoprotein (HDL) particles. The HDL is known as the “”good”” cholesterol, as it removes excess cholesterol from tissues and is therefore considered to be protective in the development of cardiovascular disease and diabetes, and people with low levels of the good HDL cholesterol have an increased risk to develop these diseases. Dr. Willeke de Haan is working to understand how these diseases are related at the molecular level. She is specifically examining the interaction between HDL and two cholesterol transporters, ABCA1 and ABCG1. Previous studies have shown that ABCA1 and ABCG1 are both involved in insulin secretion in cells of the pancreas; this provides insight into how HDL cholesterol influences and may contribute to diabetic metabolism. Her research involves both cultured beta cells, a type of cell that secretes insulin from the pancreas, as well as various mouse models of diabetes. Using these models, Dr. de Haan will determine how altering HDL cholesterol levels contributes to diabetes development by analyzing inflammation, stress, death and markers for underlying mechanisms. Her work will also provide essential insights about the function of HDL, ABCA1 and ABCG1 in the development of diabetes and cardiovascular disease, and will validate these molecules as potential targets in the development of novel therapeutic approaches to these diseases.

Signalling pathways that control the development and function of T regulatory cells

Autoimmune diseases, such as inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and psoriasis, arise from an overactive immune response against one’s own substances and tissues. If this overreaction against the body persists for an extended period of time, it results in chronic inflammation. Currently, there are no cures for autoimmune diseases; at best there are only treatments that mildly alleviate the symptoms. A patient with an autoimmune disease is typically treated with drugs to suppress the immune system, which diminishes immune responses in general. This type of treatment means that the individual becomes susceptible to infection and cancer as their immune system is effectively turned off. Dr. Scott Patterson’s research project focuses on an immune cell called a T regulatory cell (Treg). These cells have the ability to suppress immune responses and normally prevent autoimmune diseases. Since the method by which Tregs turn immune responses off is not clearly understood, Dr. Patterson’s goal is to characterize the molecular mechanisms that allow Tregs to work. In parallel, he will study how Tregs interact with other types of immune cells. Using animal models of inflammatory bowel disease and multiple sclerosis, this work will investigate the interactions Tregs have with immune cells in the body during autoimmune diseases. Gaining a greater understanding of how the actions of Tregs are controlled will be a big step in developing new therapies for autoimmune diseases and reducing the dependency on non-specific immunosuppressive drugs. Inflammatory bowel disease and diabetes each affect more than 200,000 people in Canada alone; thus, this research aims to improve the quality of life for this segment of the Canadian population.