How is the motor learning capacity of a skilled walking task affected after an incomplete spinal cord injury?

Many people who have an incomplete spinal cord injury (iSCI) have the potential to improve their ability to walk. Current training strategies are limited in their ability to target skilled walking tasks (e.g. stairs and obstacles).

Sensory function can be affected after iSCI. We believe that this could influence success at re-learning these tasks, because previous studies show that impaired sensory feedback from the leg muscles can influence how the foot moves while walking.

The goal of this work is to investigate how well people with an iSCI can re-learn a new skilled walking task, and to evaluate the impact of impaired sensory function in the lower limbs on this process.

Our findings will shed light on how reduced sensory function affects people re-learning skilled walking tasks after iSCI.

Behavioural and neural correlates of placebo responses in healthy and clinical populations

Michael Smith Foundation for Health Research/Lotte and John Hecht Memorial Foundation Post-Doctoral Fellowship Award

Placebo effects pose challenges to the conduct of clinical research. Double-blind randomized placebo-controlled trials can demonstrate superiority of an active intervention to a placebo. However, in some cases placebo control / complete blinding is difficult or impossible. For instance, in invasive or surgical interventions, placebo use raises ethical questions.

Susceptibility to placebo effects varies substantially across individuals: some experience pronounced placebo effects, while others show little or no response. Sources of this variation are poorly understood. Recent evidence from basic research has pointed to the role of reward expectancy and neural reactivity to rewards as key mechanisms of placebo response.

We seek to identify predictors of individual placebo responses in a sample of healthy volunteers, focusing on reward expectancy and reactivity. We will also examine individual variation in placebo response in an ongoing randomized controlled trial of an endovascular procedure in multiple sclerosis at UBC.

Understanding individual variation in placebo response could ultimately be used in clinical research:

  1. To model placebo-related variance of patients in clinical trials where placebo control is impossible or problematic
  2. To guide selection of patients for clinical trials

Upstream regulators of the Hippo signaling pathway in liver development and cancer

Liver cancer is the fifth most common cancer and the leading cause of cancer deaths worldwide, primarily because of late diagnosis and scanty therapeutic options. Animal studies have demonstrated that the Hippo intracellular signalling pathway is critical in regulating liver size and liver cell fate and is a potential tumour suppressor in the liver.

Loss of cell-cell adhesion is associated with the progression and poor prognosis of liver cancer. In this project, we will explore whether loss of cell-cell adhesion regulates Hippo signalling in liver cells. We are particularly interested in how loss of cadherin molecules can regulate the Hippo signalling pathway and subsequently contribute to liver development and cancer. The findings generated from this proposal will increase our understanding of the underlying molecular mechanisms involved in liver development and tumourigenesis.

Extrinsic versus intrinsic regulation of tooth replacement in reptiles: Applications to tooth regeneration in mammals

Reptiles replace their teeth continuously throughout life, as did early mammals, whereas modern mammals do not. If the ability for continual tooth renewal is latent in the mammalian genome, there is potential for the ability to regenerate and replace human dental tissues or whole teeth. This project will use an animal model (the leopard gecko) to seek the triggers that recruit the stem cells that are presumed to initiate replacement teeth.

Possible triggers could range from tooth loss or wear to changes in gradients of molecules secreted by the dental tissues that dictate position and the rate of tooth development. Analysis using high resolution synchrotron scanning and pulse-chase labelling will be compared to studies on tooth extraction previously carried out on iguanas at the Royal Ontario Museum.

Role of LTR retrotransposons in shaping the transcriptome and the epigenome of the mature oocyte and of the embryo

Long terminal repeat retrotransposons (LTRR) are the relics of parasitic DNA sequences that are present in the genomes of all mammals, making up about 8 percent of the human genome. They are usually inactive due to chemical modification of their DNA or of the proteins that bind to them. However, certain LTRR are active in specific tissue types and are thought to influence the activity of nearby gene sequences. LTRR are particularly active in the cells that give rise to eggs and sperm and in the early embryo, as well as in cancer cells.

This project will examine LTRR activity in mice using advanced DNA sequencing techniques. We believe the activity of certain LTRR during development of egg cells turns genes on that are important for normal egg production and in the developing embryo.

Our goal is to elucidate how LTRR help drive of gene expression in early embryonic development. This will help us better understand the role that they may play in infertility and potentially in cancer in humans.

Characterization of the acute morphological response of brain microglia to decreased oxygen levels and study of the mechanisms underlying microglial dynamic motility

This work will investigate three aspects of the role that the immune cells of the brain (microglia) play in stroke — a disease affecting more than 50,000 Canadians every year. First, it will characterize the acute reaction of microglia to low oxygen levels. Second, it will analyze the molecular mechanism by which microglia extend filopodia, thin actin-rich protrusions essential for their role in sensing brain damage. Third, it will examine how microglia, unlike other types of brain cells, can retain their highly dynamic function for several hours in the complete absence of glucose, widely considered as essential for brain energy.

A randomized controlled trial examining the effect of aerobic exercise on cognitive decline and brain region volumes in older men and women with mild cognitive impairment: Possible interaction between sex and BDNF polymorphisms

Michael Smith Foundation for Health Research/ Pacific Alzheimer Research Foundation Post-Doctoral Fellowship Award

Worldwide, one new case of dementia is detected every four seconds; there is currently no effective drug therapy. Given the greater prevalence of Alzheimer's disease and its faster rate of progression from mild cognitive impairment to Alzheimer's disease in women compared to men, it is essential to assess sex differences in studies relating to dementia to foster development of successful sex-specific, non-pharmacological interventions.

Results from randomized controlled trials in older adults suggest that aerobic training can enhance functioning in certain cognitive domains. Importantly, exercise efficacy differs by sex, with women showing greater cognitive changes. The sex difference may be related to brain derived neurotrophic factor (BDNF), a growth factor involved in brain health and a mediator of the cognitive-enhancing effects of aerobic training. Women, compared to men, have greater declines in BDNF with increasing age.

The beneficial effects of aerobic training on cognitive decline are modified by the Val66Met polymorphism in the BDNF gene, which leads to altered secretion of BDNF. Furthermore, aerobic training alters stress hormones differently in women and men, and women Val66Met carriers have heightened stress responses compared to men.

The main aim of this project is to determine whether sex and the BDNF polymorphism influence aerobic training efficacy in ameliorating cognitive decline and brain tissue atrophy in older people with mild cognitive impairment, a risk factor for dementia. We will also consider whether the beneficial effects of aerobic training might be mediated through alterations in stress hormones in a sex- and Val66Met-dependent manner.

We will share the results of the effectiveness of aerobic training with practitioners and with policy makers in institutions such as Vancouver Coastal Health during educational sessions to help improve patient treatment and care.

Global epidemiologic study of air pollution exposures and cardiovascular and respiratory disease in the Prospective Urban and Rural Epidemiological Study

Non-communicable diseases cause 63 percent of all deaths, with cardiovascular and respiratory diseases (CVD/RD) accounting for most of these. Outdoor and household air pollution (OAP/HAP) contribute greatly to this global burden: they are responsible for seven million deaths and 10.3 percent of disability-adjusted life-years annually worldwide, largely due to CVD/RD. Our aim is to conduct the first worldwide health study of air pollution impacts on CVD/RD, using an existing large international cohort: the Prospective Urban and Rural Epidemiological Study.

We will use novel satellite-based approaches and targeted air pollution monitoring to estimate OAP levels. Household air pollution will be estimated using detailed information already collected on heating/cooking methods, fuel types and ventilation practices within study participants' homes. We will then determine the associations of pollution exposures with measures of CVD/RD as well as key relevant risk factors such as blood pressure and lung function. This study will provide a worldwide analysis to allow us to make inferences about air pollution and related diseases in the context of a large number of other risk factors.

Understanding the spatial and contextual inequities of health access and use by people living with or vulnerable to HIV in British Columbia

Access to health care services is critical to improving the health and well-being of people living with or vulnerable to HIV. Factors such as density of services or neighbourhood violence play a substantial role as barriers or facilitators to health care access in broader populations, but limited research is available to show that this is also true for people living with or vulnerable to HIV. This study will investigate, within BC:

  1. The distribution of access and use of health services, especially health services in HIV testing and treatment.
  2. The barriers and facilitators related to access.
  3. How to develop a rigorous methodology to capture, quantify and analyze data on access and use of health services.

The proposal will draw data from several large, multi-year studies conducted by the BC Centre for Excellence in HIV/AIDS and will link to external datasets for the development of key measures. This project will focus on analyzing data regarding health care services utilization across different regions in BC over time. The proposal aims to improve access to services for earlier diagnosis and improved treatment for people living with HIV.