Research Location: University of British Columbia - Vancouver Campus

The neuroscience and molecular genetics of mosquito chemosensation

Mosquitoes are the deadliest animals on the planet. Many species use sophisticated sensory systems, including smell and taste, to locate human beings and other animal hosts in their environment as a source of blood. When they blood-feed, they can transmit microorganisms that cause human diseases including malaria and dengue fever. After converting a blood-meal into eggs, a female mosquito must find an appropriate body of water to lay eggs where her offspring will thrive. Selecting an egg-laying site is an important part of the mosquito lifecycle, since the juvenile larval and pupal stages are aquatic and cannot move from where they hatch. Mosquitoes do not fly far, and so their choice of breeding site strongly influences where they can be found as adults and thus, where they can transmit disease.

The goal of my research is to understand how mosquitoes use their sense of smell and taste to make decisions about who to bite and where to lay eggs. I use techniques to modify their DNA and to look at the activity in their brains under a microscope. Ultimately, this research will help us understand why some mosquitoes are more deadly than others and provide the basis for mosquito control strategies such as traps and repellents.

Ventilation heterogeneity in asthma, COPD and asthma-COPD overlap: oscillometry and pulmonary MRI

Airways disease is a hallmark finding in both asthma and chronic obstructive pulmonary disease (COPD). Although tobacco cigarette smoking is the largest known cause of COPD, recent studies have revealed that 10% of patients with life-long asthma may develop COPD later in life without ever smoking. The mechanisms underlying asthma transition to COPD are unknown. To better understand this transition, this proposal will use 129Xe magnetic resonance imaging (MRI), computed tomography (CT) imaging and oscillometry to measure airway abnormalities in patients with asthma, COPD, and asthma-COPD overlap. These measurements will provide a better understanding of airway abnormalities that contribute to development of COPD in these patients with asthma. COPD is the most common cause of hospital admission in Canada and treatment costs in BC alone are estimated to be over $600M/year. The results generated from this proposal may identify new ways to treat COPD or halt its development in patient with asthma, contributing to reduced hospital admissions and costs related to COPD.

 

End of Award Update – March 2024

 

Results

With the emergence of long COVID, we pivoted our novel lung imaging methods to investigate the lungs of people who experienced COVID-19 infection with persisting, long term symptoms over 1-year after infection. In collaboration with colleagues at the University of Kansas Medical Center and Duke University, we created a multi-centre dataset of patients with long COVID to better understand how long COVID may differ across different patients. We used xenon gas magnetic resonance imaging (MRI) to measure how effectively the lungs of patients with long COVID were performing gas exchange (the main function of the lungs). Our results showed that there are 4 different sub-types of long COVID that have different lung abnormalities. We anticipate that the xenon MRI results can be used to help determine appropriate treatment for patients experiencing long COVID.

 

Impact

In our centre, the xenon MRI results have been used to help determine appropriate for different patients with long COVID. Our results uncover the lung-specific abnormalities that are related to long COVID.

 

Potential Influence

We anticipate these results will help to better understand and classify patients with long COVID, towards appropriate treatment and alleviating patient symptoms.

 

Next Steps

We are using similar xenon MRI methods to investigate other forms of lung exposures including cigarette smoking, cannabis smoking, and vaping.

 

Useful Links

https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023

Vitamin C-induced epigenomic remodeling as a preventive therapy for leukemic transformation

Despite the overall improved diagnostics, standard of care and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and still only 28% of them reach 5-year overall survival. The hypothesis that drives my project is that mutations which affect DNA-modifying enzymes disrupt a methylation-based control mechanism that regulates gene expression in a way that halts the normal cellular differentiation process. The discovery that vitamin C acts as an enzymatic co-factor that is able to revert this methylation defect in affected cells, provides a unique opportunity to transfer this knowledge to the development of novel, less toxic treatment strategies for patients that harbour these mutations. Within the scope of this project, I plan to explore whether and to which extent I can restore the normal DNA methylation signature in patient-derived leukemic cells in mice, either through vitamin C treatment alone or in addition to Health-Canada approved AML drugs. Further, I will explore the potential of vitamin C treatment to delay or prevent the transformation of not yet leukemic cellular states towards myeloid malignancy.

 

 

End of Award Update – August 2023

Most significant outputs

The most exciting results are yet to come: two manuscripts are currently in preparation to be submitted to Genome Biology and Leukemia within the year.

 

Impact

Despite the overall improved diagnostics, standard of care, and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and only every third patient reaches 5-year overall survival. An observation that formed the foundation for this project is the frequent occurrence of mutations in AML cells which affect enzymes that contribute to a special control mechanism that regulates if and how much of a gene is read from our DNA to produce functional proteins. This control mechanism involves the precise placement and removal of “methylation marks” – either directly on top of the DNA strands or at proteins that help to organize the DNA into the three-dimensional structure we call chromosomes. If the placement or removal of these methylation marks is altered, protein production and cell survival mechanisms are disturbed as a consequence – a characteristic which we often observe in cancer cells. In the past, our lab contributed to the discovery that vitamin C acts as a co-factor that helps to re-activate the enzymes that deposit and remove methylation marks, even despite their mutations. Thus, treating affected AML cells with vitamin C can help to revert their methylation defect, which directs their gene expression to a healthier state and causes cancer cells to die under controlled laboratory conditions. As vitamin C is a non-toxic, well-tolerated, widely available, and cost-effective substance, its potential anti-cancer effect provided us with a unique opportunity to test whether this knowledge could be translated into effective but less toxic alternative treatment strategies for AML patients who harbour these mutations.

 

Within the scope of this Health Research BC and Lotte and John Hecht Foundation co-funded project, we have created murine leukemia model systems that allowed us to confirm the vitamin C anti-leukemic effect in living organisms. Interestingly, while studying these models more deeply, we observed that not all cells within a pool of leukemia cells responded equally to vitamin C – whereas most cells matured and died, there seemed to be some cells that were able to survive the treatment despite carrying the same disease-initiating mutations. This observation directly impacts the potential to utilize vitamin C in a therapeutic setting, arguing that even among AML cases that display the same disease-driving genetic abnormalities, not all patients will respond to vitamin C. Also, these findings are consistent with clinical observations, where historically, vitamin C was reported to be both highly effective and not effective at all in a series of trials in the 1970’s and 80’s that assessed the activity of vitamin C against terminal stage solid cancers.

 

Potential Influence

In the remaining months of finalizing this project, we are focusing on identifying what makes some cells sensitive and others tolerant to vitamin C, despite the presence of the same disease-driving mutations. Therefore, we have selected individual cells from a pool of mutation-positive AML cells which display the ability to produce a leukemia-like myeloid cell hierarchy in a culture dish. Through repeated treatment and testing, we could identify both model hierarchies that repeatedly tolerated or succumbed to the presence of vitamin C. As each cell within a model hierarchy stem from a single ancestor cell, we hypothesize that it is the maturation state of the ancestor cell – in combination with the present mutations – that mediates the observed differential vitamin C responsiveness. Further, we argue that we will be able to observe this difference in maturation state in a cell or a hierarchy’s DNA methylation patterns. We are working to confirm this hypothesis to define a diagnostic molecular signature (a so-called biomarker) that might help decide which AML patients can benefit from vitamin C in a clinical setting.

 

Next Steps

This research will be continued in the Hirst lab; however, I will move on to a new position soon as the time I am allowed to work as a postdoctoral fellow in Canada is coming to an end

Resisting Vascular Cognitive Impairment: The Effects of Resistance Training on Myelin and Blood-based Biomarkers of Neuroplasticity in Older Adults

We are studying if strength training exercises can reduce myelin loss and preserve cognitive abilities in adults with cognitive impairment due to vascular risk factors (e.g., high blood pressure), also known as vascular cognitive impairment (VCI).

Worldwide, VCI is the second most common cause of dementia and it is associated with myelin loss. Myelin is a component of neurons critical for transmission of brain signals. Thus, myelin is important for the maintenance of cognitive (i.e., thinking) abilities. Animal studies suggest myelin loss may be minimized with physical exercise. The objective is to determine whether strength training (e.g., lifting weights) is an effective strategy for slowing down myelin loss in persons with VCI.

We will conduct a 12-month study with 88 adults with VCI; half will receive strength training and half will receive balance and stretching exercises. At the end of study, the two groups will be compared on myelin content and cognitive function. Reducing myelin loss could preserve cognitive abilities in adults with VCI and reduce their risk of dementia. Our proposal is also timely as the prevalence and burden of VCI will only increase with the world’s aging population.

Promoting mental health in immigrant, refugee, and non-immigrant children: A British Columbia intergenerational population cohort study

Mental health problems are estimated to be the most common disabling condition among adolescents worldwide, with children growing up in socially disadvantaged homes having up to three times the risk of mental health problems compared to children without such disadvantage. Studies show a high degree of intergenerational stability in these patterns, with social stressors putting particular subgroups of children at higher risk from the earliest stages of development. Immigrant and refugee children make up a significant proportion of the BC child population, and have a unique set of circumstances that may increase or decrease their risk of mental health problems as they reach adolescence. In BC, an established system of child development monitoring paired with new data linkages to provincial health, immigration, and Statistics Canada records create a globally unique opportunity to investigate continuities from maternal mental health problems to childhood emotional symptoms and adolescent mental health problems, for immigrant, refugee, and non-immigrant children. The purpose is to identify opportunities to break these continuities, informing the timing and design of preventative interventions to promote population mental health.

End of Award Update: December 2022

 

Most exciting outputs

This project opened a door for me to contribute to two integrated knowledge translation studies monitoring family, child, and youth
mental health during the COVID-19 pandemic. Working together with researchers and stakeholders from public mental health and
government, we brought urgent attention to pandemic-related population mental health trends among BC families and young people
through research reports, a policy brief, an op-ed, media interviews, and eight published articles. I was excited to at the same time
complete my original study on mental health among immigrant, refugee, and non-immigrant children and present these results at the
International Population Data Linkage Network Conference in 2022. Findings from this study suggested that BC children with
immigration backgrounds enter school with lower emotional health than children with non-immigration backgrounds and are likely to
benefit from increased social supports.

Impacts so far

Our research on child and youth mental health during the pandemic was referred to during a Debate of the BC Legislative Assembly
and referenced in a BC Ministry of Education report on Key Principles and Strategies for K-12 Mental Health Promotion in Schools. I
also had the opportunity to present this research to over 100 health professionals through the Centre for Health Evaluation and
Outcome Sciences Work in Progress seminar series, drawing attention and inviting conversation around the pandemic recovery
response for supporting the mental health of families and young people in BC.

Potential future influence

The connections I have made with researchers and stakeholders through this award have initiated a pathway for what I hope will be
many future opportunities to synergize between research, health services, and policy to make collective population health impacts at a
systems level.

Next steps

I will continue collaborating with colleagues and bridging connections between research and practice in my new role in a health
services research and evaluation position. Results from the immigration mental health study have been selected for submission to a
journal special issue and will hopefully become available in 2023!

Useful links

Related videos

Watch this presentation on the mental health impacts of the COVID-19 pandemic on students, parents, and teachers, produced for the Centre for Health Evaluation and Outcome Sciences (CHÉOS) Work in Progress Seminar Series, featuring Anne Gadermann, Kimberly Thomson, and Monique Gagné Petteni.

 

Development of Novel Alpha-amanitin Analogs for Targeted Cancer Chemotherapy

New toxins for incorporation into treatments known as antibody-drug conjugates are urgently needed to ensure therapeutic action. These antibody-drug conjugates consist of an antibody, designed to target a specific group of cells, attached to an active drug that elicits a desired cell response. While most emergent payloads for clinical application target tubulin, making them redundant, the death cap mushroom contains a toxic peptide called alpha-amanitin with unique biological activity. Amanitin presents its toxicity by preventing the conversion of DNA to RNA, a process required for protein synthesis. This inhibition ultimately leads to cell death.  Amanitin’s high toxicity provides potential for a low dose cancer therapeutic if general toxicity to non-cancerous cells can be avoided. I seek to investigate the feasibility to harness amanitin’s bioactivity while delivering the toxin specifically to cancer cells by attaching a targeting agent. In order to facilitate these investigations, I will develop a scalable method to generate substantial amounts of the toxin. By utilizing this targeted approach, we anticipate a cancer cell-specific delivery of the toxin, which in turn would attenuate the off-target effects and general toxicity.

Engineering the design of regulatory T cell therapy in transplantation

Transplantation is a cure for end stage organ failure, but a successful transplant requires a life-long use of immunosuppressive drugs to prevent organ rejection. The resulting lower immunity leaves patients in a complex medical condition because increases the risk for infections and cancer.

A specific type of immune cell, called regulatory T cells (Tregs), moderates the reactivity of the immune system and favours the transplanted organ acceptance. However, to maximize the use of Tregs as therapy, Tregs need to specifically recognize proteins on donor organs. A method to engineering Tregs to be specific to donor-organ is introducing a chimeric antigen receptor (CAR). However, currently available CARs may not work properly in Tregs and in a transplantation context.

This project aims to build this method by using different gene engineering strategies to maximize the success, safety and applicability of this technology in order to reduce the need of immunosuppressive drugs. The fine-tuning of Treg-based therapies for their use in transplantation could have important benefits to the health and life quality of persons with a transplanted organ, and could mean a huge advance in regenerative and personalized medicine.

Evolving Anxiety and Depressive Symptoms in Children Born Very Preterm: Brain, Stress Regulation and Parenting

Anxiety and depressive symptoms are the most common mental health problem in children born very preterm (24 – 32 weeks gestation).  Our previous work found pain-related stress of frequent daily procedures during hospitalization across a period of rapid brain development and programming of stress hormone (cortisol) expression to be associated with later anxiety/depressive symptoms. Longitudinal studies examining how this vulnerability develops across early childhood in this population are scant. In an internationally unique longitudinal cohort of children born very preterm, I will examine whether early pain-related stress and neonatal brain development interact with levels of cortisol across childhood, altering trajectories of anxiety and depressive symptoms, at ages 1.5, 3 and 4.5 years, differentially for boys and girls. Moreover, I will identify specific parent interactions that may reduce anxiety/depressive symptoms across development. By identifying parent interactions that improve child outcomes at multiple levels (brain, stress and behavior), my research will lead to development of inexpensive, practical ways for parents to help their children, benefitting families in B.C. and beyond.

Viral Determinants of Natural Human Cytomegalovirus Transmission

Cytomegalovirus (CMV) is a virus that is present in 50-90% of adults globally, depending on the region. When a woman either becomes infected for the first time or reinfected during pregnancy, she may pass the infection to her fetus, which often causes hearing loss and intellectual disability in the child. CMV is the most common congenital infection worldwide. Women usually become (re)infected with CMV from virus shed by young children but a better understanding of how children transmit CMV to mothers is critical for designing strategies to prevent congenital CMV. 

We aim to determine how much shedding of the virus in saliva and urine of young children is required to transmit the infection to their mothers and what strains of virus successfully infect. To achieve this, we will collect samples from new mothers and their children for 1 year in Nairobi, Kenya, where rates of CMV infection are very high. Statistical testing will be used to evaluate risk factors for child and maternal (re)infection with CMV. 

This research project will provide invaluable information on CMV transmission and will inform the development of a vaccine to prevent maternal (re)infection and the resulting harm to children from congenital CMV infection.

Bone Marrow Lesions in Osteoarthritis and Their Relation to Cartilage Contact and Stresses

One in eight Canadians suffers from osteoarthritis (OA), a debilitating joint disease that frequently includes bone bruises, known as BMLs. The question we want to answer is, do BMLs result from changes in muscle strength and coordination, or poor condition of ligaments (connecting tissues) or cartilage (smooth joint lining) that cause the cartilage loading to increase? This study investigates whether BMLs might be a result of the loading environment of the knee. Though the exact cause of these bruises is not known, they have been linked to increased pain and worsening of OA. This study will measure the size and location of BMLs in people with OA and relate them to cartilage contact and stress (loading over an area). A unique standing Magnetic Resonance Imaging Scanner (MRI; i.e., looking inside the body with powerful magnets in an upright position) will be used to image OA patients during a knee bend. The BMLs will be mapped over the contact areas and stresses. Findings will provide insights into what positions (e.g. depth of a knee bend) yield contact and stress closest to the BMLs. If BMLs are linked to loading, clinical changes can be made to loading (e.g., bracing) or drugs may be taken to intervene.