Structural exploration of locked nucleic acids (LNAs) for incorporation into anticancer oligonucleotides

Antisense oligonucleotides (AON) are short lengths of RNA or DNA molecules which are used to change gene expression to treat diseases like cancer and Parkinson’s disease. Like DNA, AONs are made up of chains of nucleotide units, but to make them useful as drugs, these nucleotides have to be structurally changed. Locked nucleic acids (LNAs) are a very useful type of altered nucleotide unit, since they are not broken down as quickly in the body, and attach strongly to the gene they are targeting. The problem with LNAs is that they are very difficult to make, so it is hard for chemists to make a lot of different changes to the structure of LNAs in order to find the best one to use in AONs.
The Britton research team recently discovered a new way to make LNAs very quickly and easily, in large amounts, from simple compounds. Using this new technology, we want to make a large number of structurally unique LNAs and, test them to find the best ones to use in AONs for the treatment of cancer.

Healing indicators: Developing community-based Indigenous health assessment

Healing Indicators is a project that aims to improve health policy and assessment processes by creating tools that centre communities and Indigenous knowledge. The work is in response to the need to better assess the health impacts of resource development in Indigenous communities. This project is in partnership with the British Columbia First Nations Health Authority and Simon Fraser University, and is deeply committed to engaging in Indigenous methodologies, land-based health and healing, and health justice. It features an approach that strives to decolonize public health: the research approach is integrated, connecting land-based perspectives on health and wellness, and cultural foundations into population health reporting.

The question this research asks, is “What principles and processes are needed to create and develop indicators relevant to First Nations in relation to resource development and related policy?” Research will help support Indigenous health assessments through the collaborative creation of land-based healing indicators, that prioritize Indigenous perspectives and needs through community-based research. A goal of this work is to undertake culturally safe research in an applied health sciences context.

Examination of Long QT Syndrome causing variants in induced pluripotent stem cell-derived cardiomyocytes to evaluate novel therapeutic treatments

The rhythmic beating of the heart requires coordinated electrical activity that causes the heart to contract and relax. The electrical activity is controlled by proteins in the membranes of heart cells that form ion channels. Failure of channels to work properly is associated with abnormal heart rhythm, heart attack and sudden death. Long QT Syndrome (LQTS) is a condition that affects 1:2000 people and often results from inherited mutations in one of the heart channels. However, determining whether a mutation will cause the individual serious heart problems is still a major challenge. By using cutting edge technology, like induced pluripotent stem cells and CRISPR, we can recreate patient mutations in cells in the lab and turn them into beating heart cells. Specific techniques can be used to look at individual heart cells, as well as heart cells in a layer that beat together. The properties of the cells can be measured so that the effects of the mutations can be understood, and so that newer specific drugs can be tested to see if they are effective against different mutation types. The results from this research will help inform clinicians on how to better help patients with LQTS and potentially identify new, better treatments.

Effect of age-related spinal degeneration on older adult spinal cord injuries

Spinal cord injuries (SCIs) are becoming more prevalent in older adults, and the number of older adults is rapidly increasing. This is a challenge for healthcare professionals because the existing health issues and poor health of older adults may limit invasive surgical treatments. The most common form of SCI seen in older adults is caused by the neck extending beyond its typical range, damaging the spinal cord in a pattern that is different pattern than what is seen in younger adults. It is known that the risk of spinal cord injury and observed tissue damage is worsened by age-related degeneration in the spine; however, there is limited understanding of how these degenerative changes alter tissue damage caused by an SCI. The proposed study will consist of three objectives: (1) to measure the type and amount of degeneration typically found in older adults, (2) to simulate the spinal cord injury and use it to predict how tissue will be damaged (3) to predict how the tissue damage changes when the model includes spinal degeneration.

Investigating the role of sleep disruption in the progressive memory loss associated with Alzheimer’s disease

Alzheimer’s disease is the most common cause of dementia and a leading cause of death in Canada. Unfortunately, there are currently limited treatments available for this devastating disease. Recently sleep has been shown to regulate important aspects of Alzheimer’s disease pathology and is emerging as a promising target for novel interventions to prevent and slow disease progression.

To identify how changes in sleep and the body’s biological clock contribute to the cognitive deficits associated with Alzheimer’s disease, we will conduct a combination of preclinical experiments to evaluate causal mechanisms and clinical studies to evaluate the same processes in patients diagnosed with Alzheimer’s disease.

The ultimate goal is to determine whether treating specific aspects of sleep disruption is an effective therapy for Alzheimer’s disease, which will help identify new treatments to prevent the progressive memory loss, improve the health and quality of life of patients and their families, and reduce the economic burden of the disease.

Exploring mechanisms, pathways, and mitigation strategies to prevent loneliness, social isolation, and their deleterious health impacts

We experience hunger so we eat, thirst so we drink, tiredness so we sleep, and loneliness so we find social connection. Social needs are fundamental to humans and when we are lonely the body’s central stress response system is dysregulated. As a result, our capacity to manage stress, inflammation, and energy reserves is reduced. The end result: lonely people live shorter and sicker lives.

In the wake of COVID-19, which itself manifested in an era of already increasing social isolation, it has never been more important to study loneliness. Yet, while a robust literature base has examined loneliness in older adults, we still know very little about what we can do to respond to experiences of loneliness across the life-course. This is particularly true in marginalized populations, such as gay, bisexual, and other men who have sex with men (gbMSM), who are especially vulnerable to social exclusion and related stressors, but they also exhibit unique coping strategies that may buffer these effects.

My research will help us better understand the epidemiology of loneliness among gbMSM in order to prevent its deleterious effects on these individuals, their communities, and the broader population in the wake of COVID-19.

Informing the future of primary care: Virtual care, workforce optimization and the learning health system

Primary care is the foundation of strong health systems, ensuring people stay healthy and get care when needed. However, timely access to high-quality primary care is an ongoing problem in British Columbia and other provinces.

My program of research aims to ensure that all British Columbians can access quality primary care how and when they need it. The central project I lead uses information from interviews with health professionals (physicians, nurse practitioners and nurses) and patients; data from the health system; and provincial policy documents to study access to, experiences with, and outcomes from virtual primary care. Complementary research will inform modernization of the primary care workforce and informing ideal deployment of providers in team-based models in the context of COVID-19 and beyond. Finally, I lead work about implementation of “learning health systems” to support continuous improvement and innovation in primary care and across the health system more broadly.

My work follows an integrated knowledge translation model; I work with a team of researchers, policy makers, clinicians and patient partners to co-produce knowledge and address important and relevant questions that are driven by their combined input.

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).

Healing Indicators: Research in Indigenous health impact assessment and self-determination

This Health System Impact Fellowship is co-funded by CIHR, MSFHR, and First Nations Health Authority (health system partner), to help build BC’s health policy research capacity for the integration of policy research into decision-making.

Healing Indicators is a research project that aims to improve health assessment policy. It addresses the need to create tools that centre communities and Indigenous knowledge in the assessment of the health impacts of resource development. The project is grounded in community-based Indigenous methods, with the purpose of developing land-based wellness indicators. The work draws on self-determination, culture, kinship, community, and land to inform and define health and wellness in a First Nations context. As a research program, Healing Indicators is committed to engaging land-based healing and health justice and features a decolonial ‘two-eyed seeing’ approach, with one eye informed by Indigenous ways of knowing, and the other western science. Progressing land-based indicator research is important within the context of the First Nations Health Authority’s “Public Health and Wellness Agenda.” Land-based health indicator development requires emergent community-based methods and design that is inclusive of leadership from Indigenous peoples. The impact of this collaboration is the promotion of critical Indigenous health research, with opportunities to expand on policy gaps in relation to land-based wellness and Indigenous health assessment. Asset-based work, such as this, is relevant within the context of provincially acknowledged widespread racism within the health care system in British Columbia. This work is also significant to the provincial commitment to implement the Declaration of the Rights of Indigenous Peoples (DRIPA 2019). Healing Indicators is a collaborative research project designed to promote community-led health through land-based indicator development to inform self-determination and wellness in collaboration with the First Nations Health Authority.

Source: CIHR Funding Decisions Database