Attention-deficit/hyperactivity disorder (ADHD) is the most frequently encountered childhood onset disorder in primary care settings. ADHD is characterized by certain behaviours, most commonly: inattention, hyperactivity, and impulsiveness. Although preliminary research indicates that the biological roots of ADHD may involve certain areas of the brain, the link between the cognitive and behavioral manifestations of ADHD and its neural basis is poorly understood. Research shows that the midbrain’s dopamine system — a neural system associated with reward learning and reward-related behavior (reinforcement learning) — is abnormal in children with ADHD. To date, however, there has been little research regarding exactly how the disturbance of the dopamine system leads to this impaired reinforcement learning. Dr. Clay Holroyd is interested in the neurobiological mechanisms that underlie cognitive control — how people regulate their attention, thoughts, and actions in accord with high-level goals and intentions. Specifically, he is focusing on how people detect and correct their errors and, and how they learn from the consequences of their actions. Currently, ADHD research is an important component of his ongoing research program. Dr. Holroyd is investigating impaired cognitive control, error processing, and reinforcement learning in children with ADHD. Using behavioural experiments and computational modeling, he is researching whether the cognitive and behavioral impairments associated with ADHD are the result of the transmission of abnormal reinforcement learning (RL) signals from the midbrain dopamine (DA) system to the frontal areas of the brain involved in cognitive control. Developing a greater understanding of the link between the neural impairment in ADHD and learning and behavior is an important step towards creating a common and accepted model of ADHD; one that spans multiple levels of analysis, including biology, behavior and cognition. This research will provide a greater understanding of the neurobiological mechanisms that underlie cognitive and could lead to the development of new therapeutic treatments for children with ADHD.
Program: Scholar
Patterning and Organogenesis of the Mammalian Embryo
The development of a single cell to a multi-cellular organism, with each tissue and organ having a distinct architecture and function, is truly remarkable. Cells must co-operate and communicate with one another so they divide, migrate, form connections, change their identity, and die in co-ordinated patterns. These processes are complex, thus little is known about developing embryos and the genes that regulate their development. As an MSFHR-funded scholar, Dr. Pamela Hoodless examined how cells communicate with one another during embryonic development. This work continues, with a focus on two areas: the gut and heart. Congenital heart defects occur in about one per cent of births, making it a most common form of birth defect. With genomic technology, Dr. Hoodless can look closely at the genes involved in forming the valves and septa in the heart. She has identified two genes that control the activity of other genes, known as transcription factors, and is studying the functions of these genes in valve formation. Dr. Hoodless is also working to understand how the first stem cells of the gut are formed, and how these cells change to become other organs (liver, pancreas, stomach, etc). Identified for further study are three genes that are expressed (turned on) in these tissues, but not in the development of other body tissues. Understanding how gene regulation controls the development of the heart and gut in the embryo has far reaching implications for medical therapies, ranging from refining the repair of congenital defects to promising technologies such as stem cell therapies and tissue engineering.
Germline and Somatic Cancer Genetics: Tools for population based individualized cancer care
Today’s cancer treatment is dictated by the anatomic location of the cancer, its histology, and how far it has spread. The Human Genome Project and the development of new drugs targeted against specific features of cancer cells have led to the possibility of individualized cancer care. This is a fundamental shift in cancer management and will involve integration of each patient’s inherited genetic characteristics and the molecular signature of their tumour. My laboratory uses genetic tools to predict inherited cancer susceptibility and genomic based tumour characteristics to determine therapeutic options. In British Columbia, the central referral system for cancer patients provides the opportunity to deliver equitable individualized cancer care across a whole population. I am fully committed to this challenge and dedicate my research, clinical practice, teaching, and administrative skills to this task. My clinical work occupies <25% of my time and involves the genetic based care of familial cancers. The remainder of my time is divided evenly between (1) research infrastructure development and furthering the translational research of my colleagues and collaborators and (2) the pursuit of my own research interests. My major research projects focus on the genetics and molecular pathology of hereditary cancers, with the goal of streamlining cancer susceptibility testing and identifying therapeutic opportunities for hereditary cancers and their sporadic counterparts. Current projects include the study of gastric, breast, and ovarian cancer susceptibility. My research in hereditary gastric cancer is already shaping the worldwide management of this cancer susceptibility syndrome. To develop useful laboratory tests based upon tumour characteristics, I developed and now co-direct the Genetic Pathology Evaluation Centre (GPEC) which is Canada's leading tissue based biomarker validation laboratory and a key element in the BC research landscape. My time spent directing GPEC and other such research entities is mutually beneficial as I am user of the research infrastructure I have helped to create. All of my projects are completely congruent with my stated vision of genetic based individualized cancer care for whole populations. Although this is an aggressive agenda, I believe my record in translational research during the first 4 years of my MSFHR scholarship indicates a great likelihood of future success.
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.
Mechanisms and consequences of aberrant repair in the lung
The World Health Organization estimates that between 100 million and 150 million people worldwide suffer from Asthma. The disease places a huge burden on the health-care system, with economic costs greater than of TB and HIV/AIDS combined. While less common than Asthma, Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease since there is no cure or effective therapy. In North America and Canada there are over 200,000 patients with this disease. Of these more than 40,000 die annually. This is the same number of people that die from breast cancer annually. Currently we think that the pathology of both diseases follows a pathway similar to normal wound healing, although there is progression of the disease because the normal «braking» mechanisms do not function properly. As a consequence, too much connective tissue is produced. My research focuses on the cells that line the airways, called the epithelium and the cells that produce the connective tissue, called fibroblasts. Epithelial cells are important since they are the first cell in the lung that interacts with the air and are therefore most likely to be injured. We think that if the epithelium does not repair properly, it will signal the fibroblasts to continue making connective tissue inappropriately.
Health and the Work Environment: A Program of Research for the Surveillance and Epidemiology of Workplace Injury and Illness and the Evaluation of Workplace Policies and Procedures to Protect and the …
Health Issue: Conditions in the work environment for many occupations involve hazards to health that reduce the well-being, working capacity and even the life span of working individuals. In 2005, three BC workers per 100 had a work-related injury or illness serious enough to require medical attention and time off work.
Objective: The objective of the research program on Health and the Work Environment is to provide evidence for primary and secondary prevention of work-related illness, injury and disability in order to advance the health of British Columbians. It spans three interconnected themes of a) research data development and surveillance of work-related injuries, illnesses and exposures, b) occupational epidemiology of risk factors associated with work-related injury and illness, and c) policy and program (intervention) evaluation to reduce work-related disability.
Work Plan and Innovation: The research data development and surveillance theme involves the merging of health databases with employment characteristics and work exposure data to map injury/illness rates and exposure groups and identify high risk groups in BC by occupation and industry. To our knowledge, this will be the only population-based occupational research database of its kind in Canada.
The occupational epidemiology theme involves a study of BC firefighters and the relationship between heart disease and exposure to smoke, carbon monoxide, or physical stress; and a study of BC workers in heavy industry and the relationship between back injury and exposure to heavy lifting, awkward postures, or vibration. The innovation of both of these studies involves novel job exposure assessment techniques.
The intervention theme includes an investigation of the effect of compensation procedures to reduce wait time (surgical fee incentive and private clinic surgeries) on return to work and re-injury for workers with musculoskeletal injuries; and a study to investigate if an early intervention program improves return to work or risk of long term disability for health care workers who are off work for 5 days with depression. These two projects provide unique opportunities to inform debates on a) health service delivery models in Canada for musculoskeletal conditions (the predominant source of disability) and b) early interventions for mental illness (the fastest rising source of disability).
Biology of Somatostatin
Somatostatin (SST) is a multifunctional peptide and its function including its biosynthesis, posttranslational processing, gene regulation, regulation of secretion, islet and hypothalamic somatostatin function, somatostatin metabolism, receptors, and somatostatin dysfunction in disease such as diabetes, cancer, and neurodegeneration. This proposal is the continuation of 4 separate projects dealing with processing of SST, structure and function of somatostatin receptors (SSTR), role of SST in neurodegeneration and functional interaction of SSTRs with receptor tyrosine kinases. SST exists in two isoforms SST-14 and SST-28, derived from the same precursor Pro-SST. Our efforts in this direction are to define the molecular mechanism involved in the processing of Pro-SST to SST and elucidate whether there is any sorting receptor involve in SST maturation. Since the biological effect of SST is mediated by five different receptors subtypes namely SSTR1-5 member of G-protein coupled receptor (GPCR), exhibited homo-and heterodimerization with enhanced signaling and distinct pharmacological properties than the native receptors. Consistent with these observations we would like to determine the functional consequences of SSTR heterodimerization. In the central nervous system SST function as neurotransmitter and neuromodulator. SST cellular content and SST positive neurons selectively preserved in Huntington’s disease and gradually decreased in Alzheimer’s disease. Accordingly, the role of individual SSTR subtypes in different model of neurodegenerative diseases will be determined. The use of SST analogs is clinically proven in the treatment of variety of tumor. In breast cancer decrease SSTR expression and Increased expression of epidermal growth factor receptors (EGFRs) is frequently seen. Here we would like to delineate the role of SST and SSTRs on EGF induced transactivation of EGFR and modulation of down stream signaling cascade.
The Drainage of Cerebrospinal Fluid and Development of Inflammatory Biomarkers in Acute Spinal Cord Injury
Approximately 1,050 new spinal cord injuries occur every year in Canada, primarily in young people. There are currently approximately 40,000 Canadians living with a spinal cord injury (SCI). As a physician and neuroscientist, Dr. Brian Kwon is actively involved in discovering new ways to improve the prognosis of those with SCI. Experimental treatments that have shown tremendous benefits in animal models of spinal cord injury have not translated in human clinical trials. This discrepancy suggests important differences in the biological responses to spinal cord injury between humans and animals. Within minutes of a spinal cord injury occurring, the spinal cord swells at the injury site. This swelling reduces blood flow and oxygen to the spinal cord tissue and can subsequently result in further secondary damage. Dr. Kwon is researching whether draining some of the cerebrospinal fluid (CSF) that surrounds the spinal cord will reduce the pressure on the cord, restoring blood flow and minimizing the risk for secondary damage. In a clinical trial of patients enrolled at Vancouver General Hospital within 48 hours of their SCI, CSF samples will be taken and measured for proteins that regulate inflammation. This biochemical evaluation will offer the first human description of how these inflammatory proteins are expressed following injury, leading to new biomarkers or indicators of injury severity to assist with further research. The expression proteins will be compared with the expression of proteins in animal models to determine differences in response between humans and animals. Ultimately, these insights will assist researchers in developing therapies to improve the lives of patients with spinal cord injuries.
Wild-type Huntingtin’s pro-survival function: A potential role in Huntington’s disease pathogenesis and treatment
Huntington's Disease (HD) is an Inherited brain disorder affecting approximately 1 in 10,000 Canadians that causes progressive disability with an inexorable march towards death averaging 18 years after the onset of symptoms. There is currently no cure for HD and no known treatment that affects the age of onset or the progression of symptoms. The underlying genetic defect that causes HD is now known and the mutant HD gene produces an abnormal protein called huntingtin (htt) that damages brain cells. Many research groups around the world are studying how the abnormal htt protein kills cells, but the normal cellular function of htt is not well understood. This proposal is unique in that we will examine the protective role that the normal htt protein may play in the disease process of HD. We previously demonstrated that the normal htt protein has a pro-survival function in the brain and prevents various forms of brain cell death. Our proposed experiments will determine what specific regions of htt are required for this protective role, how protein modifications of htt affect this function, and we will test what effect modulating levels of normal htt have on the progression and development of HD. Based on our preliminary results, I hypothesize that altering the pro-survival function of htt will modulate the process of brain cell injury in HD. Mapping the critical pro-survival regions of htt, investigating the mechanisms by which this function is regulated, and understanding the downstream pathways by which htt modulates brain cell death may provide novel cellular therapeutic targets for HD and for neurodegenerative disorders in general.
The pathways project: Evaluating the transition of psychiatric services from hospital to community
Deinstitutionalization is the process and implementation of the transition of mentally ill individuals to community-based care. Although the rationale for transition from hospital-based to community-based care can be understood in terms of the desire to improve the quality of life of those living with mental disorder, the reality of resettling large numbers of previously institutionalized patients in the community raises questions about the potential risks and benefits for patients, their family members, and the public. Riverview Hospital, once Canada's largest psychiatric hospital, currently cares for the most chronically ill patients in BC, all of whom will be transferred to Tertiary Regional Psychiatric Facilities in the coming years. This significant restructuring of health care delivery provides a rare, naturalistic research opportunity to document the practical, clinical, and social implications of transferring psychiatric services to community-based settings.
Prior to transfer from hospital, Dr. Tonia Nicholls’ team will conduct a detailed evaluation of each patient’s clinical (e.g. physical health, psychiatric symptoms), (b) behavioural (e.g. suicide, self-harm, aggression, activities of daily living), and (c) psychosocial (e.g. consumer satisfaction, quality of life, stigma) status. After moving into a community care setting, each patient will be re-assessed several times to determine what, if any, changes are found. The study will evaluate to what extent closing Riverview Hospital has intended and unintended consequences. Specifically, Dr. Nicholls will study rates of homelessness, criminalization, and the transinstitutionalization experiences and health system utilization (e.g. contacts with police, admissions to correctional and forensic facilities, emergency room visits) of this cohort of individuals with severe mental illness.
In addition to patient interviews, information from patients' family members and peers, as official record databases will also be used in this study. Through a comprehensive evaluation of the process and outcomes of transferring psychiatric care to community settings, her work will demonstrate the implications of deinstitutionalization at both an individual and community level and will serve to inform future practice and policy decisions.