Program: Trainee

Characterizing Arm Recovery in People with Severe Stroke (CARPSS)

In Canada, there are over 50,000 new strokes reported every year. The prevalence and severity of subsequent upper limb disability is increasing and the prospect of complete recovery is poor. Stroke survivors who lack early indicators of a good prognosis, such as movement at the shoulder or wrist, are considered unlikely to regain much arm function through rehabilitation. However, a growing body of evidence suggests that untapped recovery potential may be better assessed from brain scans.

This project will create a data set that sheds light on 'who recovers' and 'who does not recover' by examining how the severely damaged brain changes over the first year post stroke. A series of brain scans and clinical tests of motor recovery will be performed for fifty adults with severe upper limb impairment after their first stroke. Their upper limb use during training and real world settings will also be documented.

This research will support the development of personalized training approaches that maximize functional recovery following stroke.

The role and regulation of pannexin ion channels during cytotoxic edema

A primary and often fatal consequence of stroke, traumatic brain injury, and other brain insults is edema: an increase in brain tissue water content. Cytotoxic edema is a component of this process and occurs when excess ions and water enter across the neuronal plasma membrane -the semi-permeable barrier separating the intra- and extracellular space. This increase in cell volume causes membrane swelling and ultimately results in cell death.    

Presently, the cascade of events by which neuronal swelling triggers cell death remains obscure. Preliminary evidence from Dr. Brian MacVicar's lab (the host) indicates that swelling triggers cell death by activating pannexins- a class of large transmembrane ion channels. Following activation, pannexins form large pores in the membrane and allow ions and small molecules to diffuse between the intra- and extracellular compartments. Consequently, pannexins can initiate cell death by collapsing the transmembrane electrochemical gradient and/or promoting the loss of essential cellular components. The precise mechanism by which swelling triggers the opening of pannexins is unknown. Interestingly, these ion channels can be mechanically activated by membrane stretch. Moreover, membrane stretch also leads to the production of reactive oxygen species (ROS)-a group of harmful chemical agents that can directly activate pannexins.    

For the present proposal, we will test the hypothesis that pannexin activation is a crucial step underlying cell death following cytotoxic edema. Furthermore, we hypothesize that pannexins are activated by neuronal swelling through direct mechanical stimulation and/or the production of ROS.   

These hypotheses will be tested in acutely prepared rat brain slices using advanced microscopy/imaging and electrophysiology techniques. As there are few effective treatments for edema, this research could reveal new avenues for therapeutic intervention following a variety of brain insults. Considering the implications of this project for basic biomedical and clinical research, it will be essential to diffuse and disseminate our knowledge to a variety of communities. This will be done largely through symposiums/presentations at the Society for Neuroscience as well as publication in peer-reviewed scientific journals.

A primary and often fatal consequence of brain insults such as stroke and traumatic injury is edema: an increase in brain tissue water content. Cytotoxic edema is a component of this process, which occurs at the level of individual brain cells, or neurons. The cells swell up as excess ions and water enter, causing them to die. This project will build on earlier work carried out under the project supervisor, which suggests that cytotoxic edema is caused by the action of pannexins.

Pannexins are activated through unknown mechanisms when the cell membrane is caused to stretch, either chemically through the production of reactive oxygen species or mechanically. Following activation, pannexins form large pores in the cell membrane that allow ions and small molecules to pass through. They are believed to cause cell death by collapsing the transmembrane electrochemical gradient and/or by promoting the loss of essential cellular components.

We will study tissue samples using advanced imaging and electrophysiology techniques to test the hypotheses that:

  1. Pannexin activation is a crucial step underlying neuronal cell death in the brain following cytotoxic edema
  2. Pannexins are activated by neuronal swelling through direct mechanical stimulation and/or the production of reactive oxygen species

New lines of research for therapies for damage to the brain are greatly needed and some could arise from this work.

Understanding the role of information in vaccine hesitant parents’ decision-making

Vaccination has been proven to be an effective tool to combat the spread of many communicable diseases. However, recent outbreaks of vaccine-preventable diseases such as measles have heightened concern regarding parents who are vaccine hesitant (i.e. who exhibit delayed acceptance or refusal of some or all vaccines).

Understanding what types of information most influence parents is key to producing effective public health messages that will improve vaccination rates.

Working in collaboration with the Canadian Immunization Research Network (CIRN), this project will examine the relationships among health information, social context, and parental decision-making around routine early childhood vaccinations.

To understand how information interventions interact with social context to influence parental decisions about routine childhood vaccinations, we will conduct:

  1. critical discourse analysis of vaccine discussions on social media
  2. a study of vaccine-hesitant new parents, following their information use and vaccination decisions over the course of a year
  3. a population survey module on health information seeking and use

This work will complement studies by CIRN and contribute to CIRN recommendations for Canadian immunization policy and practice.

Alteration of intestinal microbiota composition and function by co-trimoxazole use and the effect of these changes on growth in HIV-infected children

Malnutrition in early life underlies almost half of all child deaths globally and has long-term negative effects on education and productivity. HIV infection further compounds these effects in sub-Saharan Africa. The World Health Organization (WHO) recommends daily use of the antibiotic co-trimoxazole (CTX) to prevent infections in HIV-infected children. In addition to reducing deaths from infections, CTX also improves growth, possibly by changing the population of "good" microbes in the intestines.

But using antibiotics on a daily basis risks emergence of antibiotic resistant microbes, which could cause disease.

This project will test the hypotheses that daily CTX use in HIV-infected children causes the population of the microbes in their intestines to show:

  1. An increase in the number of antibiotic resistance genes
  2. An increase in the number of genes that encode proteins involved in nutrient harvesting (e.g. carbohydrate digestion)
  3. A decrease in genes involved in virulence
  4. That these changes drive the effect of CTX on growth

We will analyze child growth measurements and clinical data and will characterize genetic changes to the microbiota in stool specimens using DNA sequencing methods. Data and samples were collected through ARROW, a randomized trial designed to study the impact of CTX use on a number of health outcomes in HIV-infected children in Zimbabwe.

Our goal is to understand how daily use of CTX impacts child health in a wider context and to inform WHO recommendations on CTX use in HIV-infected children.

Supporting women’s sexual and reproductive health and rights through Treatment as Prevention: Investigating the impact of structural and interpersonal violence on HIV and reproductive health inequities among women living with HIV in British Columbia

BC's ambitious "90-90-90" target for 2020 aims to ensure that: 1) 90 percent of people living with HIV/AIDS are aware of their status; 2) 90 percent of those diagnosed receive sustained treatment; and 3) 90 percent of those being treated achieve viral suppression. Access and uptake from all affected groups in BC would be needed to achieve this. This work aims to identify and study barriers to HIV testing and treatment and reproductive health services (e.g. cervical screening, mammograms, fertility and pregnancy services) among marginalized women living with HIV/AIDS (WLWHA) in BC.

Specific areas of study will include:

  • Investigating the impact on disclosure of HIV status to health care providers and intimate partners of social factors such as:
    • criminalization of drug use and sex work
    • gender-based violence
  • Investigating the spatial distribution and accessibility of sexual and reproductive health services and their impact on reproductive health outcomes (e.g. contraceptive usage, cervical screening, unintended pregnancy)
  • Exploring challenges faced by WLWHA with families, including how caregiving demands and gender-based violence affect treatment access and compliance.

The intended outcome of the work is to recommend improved service delivery methods for HIV testing, treatment and reproductive health care with an ultimate goal of informing policies and programming.

The mechanism and significance of the synaptogenic activity of amyloid precursor protein

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

Amyloid Precursor Protein (APP) is a cell surface protein that has been mostly studied in the context of Alzheimer’s disease. Much about its normal function remains unknown. APP can cause connections to form between brain cells by an unknown mechanism. We believe this happens through an interaction with synaptic organizing proteins (organizers).

This project will investigate the possibility that APP forms synapses by interacting with major organizers in the brain, namely neurexins and receptor protein tyrosine phosphatases (RPTPs).

To test this, we will use a combination of cell cultures and mouse models. We will test whether APP binds to neurexins and RPTPs and whether binding to these organizers is required for the connection-forming activity of APP. We will also compare brain cell connections in normal mice to those in mice that express an altered form of APP that cannot bind to organizers.

This study may shed light on the function of APP through detailing how it can help form connections between brain cells. If defects in connections between brain cells contribute to neurodegeneration in Alzheimer’s disease, these results could shed light on the mechanisms behind that as well.

Etiology and progression of amyotrophic lateral sclerosis: an epidemiological analysis of environmental risk factors

Amyotrophic lateral sclerosis (ALS) is a devastating disease with fatal outcomes usually within a few years following diagnosis. The progressive degeneration of the nerve cells responsible for muscle movement leads to muscle wasting and paralysis, and eventually restricts breathing. The cause of ALS is unknown and probably includes a number of external factors.

There is a relative lack of very large-scale studies with data on potential risk factors collected before ALS occurs. This project aims to assess data from the entire population of Canada to examine the effect of external factors such as military service, trauma, and medication use on the risk of:

  1. developing ALS
  2. progression of ALS

Ultimately, this research could aid in designing effective disease prevention efforts and treatment strategies.

Continuing Health Impact Assessment (CHIA) of the computer-based Drug and Alcohol Training Assessment in Kenya (eDATA K)

Tobacco, alcohol and other substance use disorders (SUD) are among the most important risk factors for the global burden of disease, with a 38 percent increase in global burden of the disease from substance use in the 20 years between 1990 and 2010, mainly driven by increased drug use (57 percent) and alcohol use (32 percent). The tobacco consumption is also worrisome considering the highest incidence of smoking is among men in low and middle income countries (LMIC), and that in the poorest LMIC households, 10 percent of the total income is spent on tobacco, to the detriment of consumption of healthy food and other essential elements for the health of the whole family.

Clinical prevention and care for these disorders are lacking in LMIC. A project funded by Grand Challenges Canada and run by NextGenU.org and the Africa Mental Health Foundation seeks to address that gap through:

  1. Piloting online training in SUD intervention for health care workers in rural and urban areas of Kenya
  2. Conducting randomized control trials (RCT) of the impact of alcohol brief intervention
  3. Determining the feasibility of sustaining the delivery of the interventions post-randomized control trials

The studies are ongoing, with screening data collected on more than 22,000 adults, enabling recruitment of 1,200 patients from October 2014 to February 2015 in 10 facilities from three counties. The clinical courses to address substance use disorders, and other NextGenU courses, are being used in 134 countries.

The screening included SUD, BMI and physical activity level (to mask the purpose of the trials and to decrease barriers from stigma).

Preliminary analysis shows that the outcomes include alcohol use reduction for the patients, and decrease in stigma from healthcare worker, as well as feasibility of sustaining the intervention post RCT.

This project will analyze the data, including the impact on quality of life, self-stigma, depression, risky sexual practices, general health and mental health status, and other substance use consumption. It will also perform knowledge translation of the clinical impact, and continue to carry out the feasibility assessment of sustaining the interventions.

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