Each year, about 75,000 patients in Canada will develop sepsis (severe infection). Although it is reversible, sepsis often causes death. Sepsis and a related condition, systemic inflammatory response syndrome (SIRS), lead to multiple organ dysfunction and are the most common reasons for admission to intensive care units. Using genetic information that became available after completion of the human genome project, Dr. Keith Walley is researching the genetic determinants of the acute inflammatory response and organ failure associated with sepsis. His aim is to clarify the genetic mechanisms which give rise to the inflammatory response and to apply this information to identify patients who are at risk for adverse outcomes based on their genotype (genetic make-up). His ultimate goal is individualized management of patients with sepsis, based on knowledge of the way their genotype will influence their susceptibility to and risk of developing life-threatening symptoms, as well as their ability to respond to treatment.
Program: Scholar
Leptin regulation of glucose homeostasis
More than two million Canadians have diabetes, a chronic metabolic disorder caused by the inability of the body to produce or properly use insulin. Obesity is a risk factor for developing type 2 diabetes, the most common form of the disease. Dr. Timothy Kieffer has uncovered links between leptin – a hormone that affects how the body manages and stores fat – and insulin producing beta cells of the pancreas, plus the liver, one of insulin’s target tissues. His research suggests there may be a defect in the interaction between leptin, fat, beta cells and liver cells. Using genetic engineering approaches, Dr. Kieffer is investigating the role of leptin in the development of diabetes and obesity, in the hopes of eventually developing novel therapeutic strategies to combat these debilitating diseases.
Mammalian organelle-membrane Type Na+/H+ exchangers
The cell is the basic unit of structure and function in the body. Many of the functions of cells are performed by particular subcellular structures called “organelles”. Acidity (pH balance) is important for organelle function and disruptions in this environment can lead to uncoordinated communication between brain cells, compromised immunity and uncontrolled cell growth or death. Dr. Masayuki Numata is studying the mechanisms for pH regulation in cells. Dr. Masayuki Numata and his research team have isolated ion transporter proteins that may regulate acidity inside organelles. Using biochemical, cell biological, genetic and immunological techniques, he is investigating how these transporters are delivered to the right destination when they are needed and how they are regulated by different factors. The research could ultimately increase understanding of the mechanisms by which brain cells transmit signals to each other and how disruptions in these signaling pathways cause damage leading to Alzheimer’s disease and other neurodegenerative disorders.
Regulation of NMDA receptors and excitotoxicity
Glutamate mediates signaling between neurons (nerve cells) by binding to protein receptors. Over-activation of one type of glutamate receptor, NMDA, can result in damage to neurons. Dr. Lynn Raymond is researching how neuronal activity and cell proteins regulate NMDA receptors, with the goal of better understanding how irregularities or disruptions in regulatory pathways are implicated in damage associated with neurological disease. Dr. Raymond is especially interested in Huntington’s Disease. This inherited neurological disorder causes progressive neurological damage in specific brain regions leading to movement abnormalities, personality changes, psychiatric disorders and memory loss. Studies have suggested that over-activation of NMDA receptors plays a major role in this selective destruction of brain cells. Dr. Raymond is investigating interactions between mutant huntingtin (the protein produced by the Huntington’s Disease gene) and NMDA receptors to gain a more detailed understanding of the causes of neuronal death in Huntington’s Disease – research that may help in the development of new therapies for this incurable disease.
Synaptic and non-synaptic modulation of neuronal excitability
Neurons (nerve cells) communicate through a process in which one cell stimulates another with an electric pulse transmitted by secreting special chemicals called neurotransmitters into the synapse (gap) between the cells. Learning and memory are influenced by changes in the strength of these synaptic connections and by alterations in the excitability of neurons (how readily they produce an electrochemical response). Abnormalities in the regulation of neuronal excitability give rise to neurological diseases including epilepsy and psychiatric diseases such as schizophrenia. Dr. Brian MacVicar is studying two aspects of synaptic transmission: mechanisms that regulate neuronal excitability and mechanisms that influence synaptic plasticity (the ability of neurons to adapt the way they communicate with each other). In one series of experiments, he is examining cells that surround neurons in the brain to determine if they influence neuronal activity through the regulation of blood flow or other mechanisms. He is also studying how past synaptic experience modifies activity in dendrites, the part of the neuron that receives synaptic transmissions. This research into how brain activity is regulated will contribute to improved understanding of many aspects of neuroscience, including stroke, mental illness and learning and memory.
Molecular controls of embryonic facial patterning
The transformation of the embryo from a mass of undifferentiated cells into a fully formed, functioning organism is a complex process. In early embryonic development, discrete buds of cells fuse to create a face. If proper fusion fails to occurs, the result is severe developmental abnormalities including cleft lip with or without cleft palate. The embryonic segments that form the face are similar in chickens and mammals. Using the chicken embryo as a model, Dr. Joy Richman is studying how the jaw is formed and what goes awry in the process to cause cleft lip. By investigating the mechanisms that designate which embryonic facial bud will develop as a particular facial feature and how appropriate growth is initiated at key times to form a face, Dr. Richman will identify genes and gene signaling pathways that underlie normal and abnormal development of the face and jaw. Such information is critical for improved treatment and prevention strategies for defects such as cleft lip.
Postural Control in individuals with stroke
Every year about 50,000 Canadians will have a stroke, which is the number one cause of neurological disability leading to impaired balance and mobility. Those affected face a seven-fold increase in hip fractures because of falls due to poor balance. Unfortunately, there are very few community-based programs to help individuals with stroke improve or maintain mobility and balance, and a lack of research assessing the effectiveness of such programs. Dr. Janice Eng is investigating the effectiveness of a 12-week exercise program for improving balance and mobility in two groups of people with stroke: a group participating in an intensive exercise program, and another group doing arm exercises. Results of her research could assist in developing guidelines for community-based exercise programs to improve the health of people with stroke, and to reduce hospital admissions due to falls.
Psychological pathways for the relationship between socioeconomic status and asthma in children
Research has shown a strong association between low socioeconomic status and poorer heath. Asthma, the most common chronic childhood condition, is more prevalent and more severe among children low in socioeconomic status. Although many factors have been proposed to explain the SES-asthma relationship (e.g. exposure to environmental allergens and irritants, gene by environment interactions, quality of medical care, etc.), these variables do not fully account for this relationship. Dr. Edith Chen is studying the role of psychological factors, such as stress, in explaining the SES and asthma relationship. She is testing whether children with asthma who have low socioeconomic status experience more stressful events and/or whether they have a tendency to interpret life events in a more threatening fashion than children from higher socioeconomic status, and ultimately whether stress helps to explain the connection between low socioeconomic status and poorer asthma outcomes. Some children with low socioeconomic status maintain good health despite adverse life circumstances. Dr. Chen is also examining whether children’s beliefs and supportive family and social networks can buffer children with asthma from the typical effects of low socioeconomic status on health. Results from this research may help improve the health of children with asthma.
A prospective transdisciplinary study of the impact of housing improvements on health: promoting global health equity through innovation and collaboration
Under the leadership of Dr. Jerry Spiegel, BC health researchers are playing an active role in addressing global health research priorities – issues that increasingly affect British Columbians as global citizens as well as individuals subject to increasingly global pressures. With a interdisciplinary team of researchers at the University of British Columbia, linked to colleagues at the universities of Victoria, Simon Fraser, Saskatchewan and Manitoba, with counterparts from Mexico, Cuba and other Latin American countries, Dr. Spiegel has developed a program of research which aims to improve world understanding of “upstream factors”, i.e. pathways whereby global forces affect health. For example, rapid urbanization is a growing global phenomenon that underscores the ongoing need for attention to the basic need for appropriate shelter. While there is a clear relationship between poor housing and poor health, little research has been done not only on the reasons behind rapid urbanization and deteriorating housing, but on the health gains that result from housing improvements. In a unique collaboration with world-class specialists in housing and health research, Dr. Jerry Spiegel is investigating the impact of housing on health. Dr. Spiegel and a multi-national, multi-disciplinary team are studying two groups in Cuba: one living in poor housing conditions that will receive state funded improvements to address hygiene, ventilation, illumination and overcrowding; and another group living in comparably poor housing that is not receiving improvements. The team is using a variety of methods — including ethnographic studies, surveys, environmental monitoring of homes and measurement of biological factors associated with health — to measure the effects of housing on health. Results from the study could be used to develop policies that will improve the health of vulnerable populations in Canada and throughout the Americas. Other international studies being conducted by Dr. Spiegel and his team address other social and ecosystem determinants of health, needed to provide valuable information to promote health in British Columbia and worldwide.
Use of T regulatory cells to induce tolerance to organ and tissue transplantation
Transplantation is the treatment of choice for many forms of end-stage organ failure and cancers of the immune system. Due to the difficulty in finding fully compatible donors, the patient’s immune system must be suppressed with drugs to prevent it from rejecting the transplanted tissue. While necessary, these drugs suppress all immune response, causing serious side effects including increased risk for infections, cancers, damage to kidneys, hypertension, diabetes and seizures. Dr. Megan Levings is looking for a way to protect the transplanted tissue without compromising other aspects of the normal immune response. She is studying a novel class of white blood cells, known as T regulatory (Tr) cells, which are thought to have the ability to selectively suppress immune responses. Dr. Levings is exploring the molecular and cellular biology of Tr cells to better understand how they develop and act to induce an immune response. Potentially, these cells might be the basis for a more directed approach to controlling rejection.