Organelle signalling in stem cell identity specification

Stem cells offer tremendous potential for tissue regeneration and uncovering causes and treatments for many human diseases. Technologies developed over the past decade now allow us to grow human stem cells in the lab and manipulate them to carry disease-causing gene mutations and turn them into any cell type of interest. My lab’s research uses these powerful tools to identify important regulators of stem cell function, particularly as they develop into cell types relevant to brain disorders. We focus on identifying the biological processes that build our brains, and biomarkers and treatment approaches for diseases.

Though the genes that regulate stem cell function are fairly well know, the impact of cell organelles, which coordinate many biological functions and are potential targets for treatment, is poorly understood. My lab is working to bridge this gap by investigating the impact of vesicle-like organelles called lysosomes on brain stem cells. Our data suggests lysosomes are critical regulators of stem cell function and brain development. Given new imaging-based tools and clinically approved lysosome-targeted drugs, studying the role of lysosomes can transform our potential to understand, diagnose, and treat brain disease.

Understanding human genome regulation through robust and multi-scale reference chromatin state annotations across hundreds of human cell types

Although researchers have identified tens of thousands of disease-associated genetic variants, the mechanisms driving most of these variants remains unknown. Most variants are believed to affect regulatory elements. However, regulatory elements are incompletely annotated and understood. Large-scale projects have recently generated thousands of epigenomic data sets. These data sets measure the regulatory activity of the genome in human cells. However, computational methods are needed to understand the link between genetic variation and disease.

We previously developed a computational method, Segway, that annotates genomic regulatory elements on the basis of epigenomic data sets. Enabled by new epigenetic data sets, this project will annotate the genome in hundreds of human cell types, and use these annotations to understand disease-associated genetic variation.

Additionally, we will develop computational methods that improve our ability to identify genomic elements. This outputs of this project will come in three forms:

  1. General-purpose software for annotating the genome.
  2. Easy-to-use reference data sets.
  3. Insights into the link between genetic variation and chronic obstructive pulmonary disease (COPD).

Healthy Children, Healthy Communities: Co-Benefits of Children’s Action on Climate Change and Mental Health

Problem: British Columbia is being increasingly impacted by climate change and therefore the health and wellbeing of children in this region are at risk, and will be throughout their lives unless action is taken.

Overview: Conducted for, by and with children, this research will answer 2 questions: How is children’s health being impacted by climate change? Can taking action on climate change through community projects, strengthen and build resilience in children, even in the age of climate change? A central focus of this work will be on mental health and wellbeing.

Outcomes: After filling a significant scientific knowledge gap about the public health impacts of climate change on children in BC, evidence gathered will be used to help develop community projects that tackle a local impact of climate change.

Impacts: This research will identify why and how certain community projects on climate change protect, and even improve, the mental health and wellbeing of children and make recommendations for how other communities can use this information to build their own healthy children, healthy community projects. These successes will be shared with decision makers to support the choices they make around climate change and health.

Real-time Combined Genomic and Epidemiological Monitoring of COVID-19 in British Columbia

Viruses accrue small amounts of genetic variation over time. By sequencing the virus, we can see this variation and use it to understand where an individual virus likely came from and how it is moving through a population. This helps public health teams to estimate how many cases are due to local transmission as opposed to imported cases. In this proposal, we will establish ways to use virus sequences to understand transmission in a high-resolution way that is not possible with epidemiological or virus sequence data alone. To do this, we will combine viral sequences with epidemiological data in new ways, establishing high-resolution pictures of transmission. We will operationalize the use of these combined datasets for real-time COVID19 public health use in BC.

“Blind Spots”: People in Prison and Precarious Housing During COVID-19

Prisons and substandard housing pose serious risks to individuals and communities during the COVID-19 pandemic. Limits on physical distancing are associated with disease outbreaks in shelters, camps, and prisons. The high prevalence of pre-existing illness in the settings places people at risk for medical complications. This project will generate evidence of ways to reduce the spread and impact of COVID-19 by analysing hospitalizations among people who were in custody or inadequate housing during the first wave of COVID-19 in BC. The project will also develop recommendations on the use of mandatory testing. The project team is drawn from established networks of researchers, decision-makers, service providers, and people who have experienced homelessness and time in custody.

Prenatal exposures to PBDEs and PFCs: Sources of exposure, thyroid effects, and neurodevelopmental effects in children

Polybrominated diphenyl ethers (PBDEs) and perfluorocarbons (PFC) are chemicals that are used as flame retardants and surfactants in a wide variety of consumer products. In animal studies, both chemical groups have been shown to have toxic effects on the thyroid and have the potential to affect fetal brain development. A small but growing body of evidence suggests similar thyroid effects may occur in humans; however, the links between these chemicals and thyroid disruption in early pregnancy, the most critical window of exposure, are still unclear. The specific effects of prenatal PBDE and PFC exposures on neurodevelopment in humans are largely unknown. Disturbingly, both chemicals are present in the blood of the entire Canadian population, including children and newborns, and the most important sources of these chemicals are poorly understood. The post-doctoral research of Dr. Glenys Webster will help fill these gaps by 1) identifying the main sources of PBDEs in maternal blood, 2) exploring whether maternal PBDE levels are associated with maternal thyroid hormone levels in early pregnancy, a time when thyroid hormones play a critical role in fetal brain development, and 3) examining the relationships between maternal PBDE and PFC levels and neurodevelopmental outcomes in one- to three-year-old children, as measured by cognition, motor function and behavior. Dr. Webster’s work will use data from two existing pregnancy cohorts in Vancouver and Cincinnati, and will link the sources of chemical exposure to chemical levels in blood to maternal thyroid effects to child neurodevelopmental effects, all within the same study populations. Understanding the public health implications of population-wide exposures to PBDEs and PFCs will provide key information for ongoing risk assessment and risk management strategies in Canada and will support the development of effective chemical regulation policies to protect public health.

Role of ciliary proteins in vision and obesity

The cilium is an extension on most cells and tissues that works similarly to a television antenna, in that it receives signals from the environment. When a mutation disrupts the function of cilia, cells no longer receive the proper environmental input. Mutations in cilia proteins have been identified in patients with clinical ailments such as blindness, obesity, diabetes and polycystic kidney disease; some are also found in syndromes encompassing all or most of these disorders. Although some of these syndromes affect entire families, the molecular and cellular causes of these disorders have not been identified or characterized; for this reason there are no therapies available. Dr. Victor Jensen aims to study and identify novel cilia genes that are associated with multiple disorders, including blindness and obesity. These results will provide essential information about the association between disease and different genes, as well as the function of cilia. This unique approach to gene discovery and characterization was developed in the laboratory of Dr. Leroux, and has already led to the discovery and understanding of numerous disease genes, including those associated with the multi-systemic Bardet-Biedl syndrome. Dr. Jensen’s research work is therefore aimed at providing novel insights into the nature and function of disease genes, a step that will eventually lead to improved treatments or prevention of common human medical ailments.

Studies Towards the Total Synthesis of Eleutherobin and Designed Analogues for Cancer Therapy

Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.

An Examination of the Risks and Health Needs of Adolescents and Young Adults with FASD in the Criminal Justice System.

Fetal alcohol spectrum disorder (FASD) is an umbrella term referring to a range of permanent deficits that occur in a developing fetus as a result of exposure to alcohol during pregnancy. FASD is the leading cause of developmental disability among Canadian children and is identified as a major public health concern in Canada. Individuals with FASD experience high rates of health related problems, including serious mental illness and substance use, homelessness, violence and victimization. In BC, the government has committed to the important goal of providing individuals living with FASD the support needed to reach their full potential in healthy and safe communities. To assist in achieving this goal, the province has called for more research to inform treatment efforts in general health and justice settings. Kaitlyn McLachlan’s research speaks to that need by providing a knowledge base specific to the risks and health needs of youth diagnosed with FASD in the justice system. The overall purpose of this study is to improve health outcomes for justice-involved youth with FASD, in part, by developing a knowledge-base about offending patterns and salient risk indicators in youth with FASD. The project will be based in BC and parallel data collection efforts will be made in additional provinces so that reliable conclusions can be made about this population. The information from this study can be used to inform the targets and timing of interventions and improve clinicians’ recommendations about risk, risk management and interventions. The knowledge gathered about mental health and substance use problems will also be crucial in determining the types of community-based services youth with FASD require outside the justice system in order to maintain good health.

Function of clathrin-based endocytic proteins during infections by extracellular bacterial pathogens

Most E. coli bacteria live within the intestines of humans and other animals where they help with normal digestion. However, certain types of E. coli cause disease and represent serious global health concerns. For example, diseases mediated by these pathogenic E. coli often lead to gastro-intestinal infections, resulting in severe and persistent watery or bloody diarrhea. These diseases affect a significant population, especially infants, in many developing countries and the associated mortality rates can exceed 30 percent. Previous research by Ann Lin and others has shown that clathrin, a protein that involves endocytosis, plays a key role in generating E. coli-based diarrhea in humans. Expanding on this research, Ms. Lin is now focusing on the identification of clathrin-associated endocytic components necessary for the development of enteropathogenic E. coli infections, using both in vitro and in vivo approaches. Because other bacteria and viruses (such as influenza), also control clathrin-based internalization mechanisms as part of their infection, Ms. Lin’s’s research will not only provide valuable insight into the mechanism of E. coli-based disease, but will also generate new avenues for the development of novel therapeutics to eradicate other infectious diseases.