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:
- An increase in the number of antibiotic resistance genes
- An increase in the number of genes that encode proteins involved in nutrient harvesting (e.g. carbohydrate digestion)
- A decrease in genes involved in virulence
- 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.
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.
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:
- developing ALS
- progression of ALS
Ultimately, this research could aid in designing effective disease prevention efforts and treatment strategies.
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:
- Piloting online training in SUD intervention for health care workers in rural and urban areas of Kenya
- Conducting randomized control trials (RCT) of the impact of alcohol brief intervention
- 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.
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:
- To model placebo-related variance of patients in clinical trials where placebo control is impossible or problematic
- To guide selection of patients for clinical trials
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.
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.
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.
Blood transfusion is a critically important medical procedure used to treat blood loss due to trauma or during surgery; it is also used in the treatment of chronic blood disorders such as thalassemia, sickle-cell disease and other forms of anemia. Due to the presence of blood antigens, however, careful blood typing is necessary to avoid the adverse and sometimes fatal reactions that may result from a mismatched blood type during transfusion. The A and B blood antigens are considered the most clinically important blood antigens. These antigens consist of carbohydrate (sugar) molecules attached to the surface of blood cells. People with type O blood lack the A and B antigens on their red blood cells and thus are often considered “”universal donors”” (not accounting for minor antigens), yet units of type O blood are frequently in short supply due to high demand. The use of enzymes to remove A and B antigens is a potential means of generating universal blood donor cells from blood types other than O. Dr. David Kwan’s research aims to investigate methods for the enzymatic removal of blood antigens from blood cells. Although enzymes that remove the A or B antigens to convert red blood cells have been discovered, they have low efficacy. Recently a new enzyme called EABase was discovered, which can efficiently remove the B antigen but only slowly removes the A antigen from red blood cells. The primary focus of Dr. Kwan’s work will be to engineer the EABase enzyme using “”directed evolution”” techniques to improve the efficiency of EABase in removing blood antigens so that it may be a more efficient catalyst for the conversion of A-, B- and AB-type red blood cells into “”universal blood cells.”” A secondary focus, in collaboration with the Centre for Blood Research, will test the use of polymer additives to enhance the rate of enzyme action. Over 15 million units (approximately 450 ml per unit) are collected for preparation of blood products in Canada and the United States per year. The ability to generate universal blood donor cells would be a breakthrough development, allowing transfusion without the need to find a positive match and tremendously improving the supply of blood while increasing the safety of blood transfusions.
