Program: Trainee

Multimodal characterization of airway remodeling with label-free nonlinear optical imaging

Michael Smith Foundation for Health Research/AllerGen Post-Doctoral Fellowship Award

The number of Canadians who will die from asthma is estimated at 200 per year and over 3 million suffer daily with the disease. A better understanding of the disease could give rise to more effective treatments.

Within the normal lung, collagen and elastin fibers provide the structural components of the airways. In asthmatic airways, the collagen and elastin fibers are disorganized and more collagen accumulates within the airway, making the airway more narrow and harder to breath through.

We will use nonlinear optical microscopy (NLOM) to understand the changes in the three-dimentional structure of the airways' elastin and collagen fibres that occur within asthma. Additionally, we will observe changes that occur inside these fibers by transmission electron microscopy (TEM).

Thus, if collagen were a "rope", we would be taking images of this rope with NLOM, and then images of each thread that composes the rope with TEM. To study the spatial distribution of the "ropes" and the ratio of collagen to elastin in asthmatic airway tissue, we will use textural analysis.

This study will give rise to results that could aid researchers in developing better asthma therapies, this improving the quality of life for millions of asthma patients.

Mirrored integrated patient practitioner journey mapping for addressing persistent health inequities lived by Aboriginal people in Northern British Columbia

Aboriginal people in northern BC live with persistent health service inequities. This research asks:

  1. What is the current character of the interface between health provision institutions and Aboriginal communities in the rapidly evolving social, cultural and political climate?
  2. In the diverse landscape of Aboriginal communities, what are the common gaps in health services and programs, and how can they be addressed in a holistic way to renew the health and well-being of Aboriginal people and communities?     

Research design heavily incorporating Indigenous methodologies, ways of knowing, and decolonizing methodologies will be used to develop a model for integrated health and a well-being journey mapping integrating both sides of the patient/practitioner interface with specific attention to:

  • Socio-cultural determinants of health.
  • The specific context of Aboriginal communities in urban, rural and remote northern BC.
  • Attention to applied methodologies and Knowledge To Action (KTA), Aboriginal KT (AKT), and integrated Knowledge Translation (iKT) strategies.

This work will:

  • Describe the nature of the current paradigm shift in health services and program provision for Aboriginal communities and identify emerging streams of new vision and work to improve their health and wellbeing.
  • Identify and explore community-driven mechanisms to renew trust at the community-institutional interface and to expand access to culturally safer programs in Aboriginal communities.

Role of allergen-experienced Group 2 Innate Lymphoid Cells in allergic lung inflammation

Allergic asthma is an incurable respiratory disease that affects more than 300 million people worldwide. Asthmatic patients first become sensitized by inhaled substances that trigger an allergic reaction (allergens). Repeated exposures to the same allergens cause allergic inflammation in the lung because allergen-specific cells of the immune system called lymphocytes acquire memory: they react when they re-encounter the same allergen.

Another set of cells, the recently identified Group 2 Innate Lymphoid Cells (ILC2s), can also trigger allergic lung inflammation. Unlike regular lymphocytes, ILC2s do not recognize specific allergens. However, experienced ILC2s can vigorously react to new allergens, causing a stronger allergic lung inflammation than they did on their first exposure to unrelated allergens. Therefore, ILC2s can acquire memory that is not specific to particular antigens.

We believe that upon allergen encounter, different subsets of memory ILC2s are generated. The goal of this research is to characterize memory ILC2s in the chronic phase of allergic lung inflammation.

The results obtained in this research would explain why sometimes the causative allergen is not identified and why asthma vaccines are not always effective. This research may lead to the development of novel therapies for chronic asthma.

The cost effectiveness of personalized medicine: Using a biomarker-driven treatment strategy for Rheumatoid Arthritis

Rheumatoid arthritis is a common lifelong disease. People with the disease suffer swelling and pain as the disease damages their joints. This leads to disabilities that can affect their ability to do day to day tasks in their personal and work lives.

The best way to slow down the damage caused by the disease is to treat it early. There are many different treatments available, but there are many people for whom each of these treatments does not work. New tests are being developed in laboratories to try and understand which treatments are likely to work for each person with the disease. These tests offer the hope that only the people who are likely to benefit from a treatment will be treated, saving money, and giving patients effective treatment earlier. What is not known is whether these tests can actually improve patient outcomes and save costs in real life.

This study plans to estimate the value to patients and the health system of paying for additional tests to determine which treatments people are given and when.

Are there indicators of Alzheimer’s disease in the eye?: New computational imaging and analysis algorithms

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

 

Alzheimer’s disease (AD) is progressive degeneration of the brain that results in loss of memory and cognitive abilities. The prevalence of the disease presents a daunting challenge — as of 2015, 46.8 million people in the world live with AD, with the number expected to double by 2035. In Canada, 14.9 percent of those 65 and older have the disease. The global health-care cost for dementia has exceeded 1 percent of the global gross domestic product (GDP).

 

AD significantly affects the quality of life for the patients and caregivers, and this makes early detection critical. However, the brain imaging required for the diagnosis is costly, and AD is often discovered only after it has progressed considerably.

 

The overarching theme of this project is finding the connection between the eye and AD, by investigating it for potential biomarkers of the disease. The eye is an extension of the brain, with the optic nerve forming a direct physical connection between the retina and the brain’s visual cortex. Recent advances in ophthalmic imaging techniques, such as optical coherence tomography (OCT), provides high-resolution 3D visualization of the inner structures of the eye, including the retina, nerve fibres, and blood vessels, in a noninvasive manner. OCT and other imaging techniques give us a comprehensive picture of the eye’s health and function.

 

We will develop image processing and analysis tools to examine chemical biomarkers, structural degradation, and functional loss in the eye that may be associated with AD. The project will potentially lead to discovery of novel AD biomarkers in the eye, and a cost-effective and accessible diagnostic tool for early detection of AD.

 

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

We know that amyloid beta, a hallmark of Alzheimer’s disease, is present not only in the brain but also in the retina of the patients, and its deposition can vary by location and comorbidity such as cerebral amyloid atrophy.

 

Why is this knowledge important?

Retina can be readily imaged in high detail, and it contains rich information about the person’s neuronal health. Retinal imaging has potential as an early and accessible screening tool for neurodegenerative diseases. Studying the mechanisms of Alzheimer’s disease pathology in the retina also gives us insight into those in the brain.

 

What are the next steps?

Professor Joanne A. Matsubara’s group at the University of British Columbia and I are continuing to collaborate to study retinal biomarkers of Alzheimer’s disease. We are currently looking into how amyloid beta affects glial cells and blood vessels in the retina.

 

Publications

Women and the criminalization of HIV – An ethnographic investigation of gendered power relations, violence and access to health care

Women living with HIV/AIDS (WLWH) have been identified as a key population of interest by the Federal Initiative to address HIV/AIDS in Canada. An October 2012 ruling of the Supreme Court of Canada upheld the criminalization of HIV nondisclosure except where both a condom is used and the person has a 'low' HIV viral load. The decision has drawn criticism as being 'gender-blind' for failing to consider the gender imbalance in negotiation of male condom use and in associated risks for violence and livelihood.

Given the prevalence of gender-based violence and ongoing HIV-related stigma, there is a need to better understand how the criminalization of HIV non-disclosure uniquely affects WLWH.

The central objectives of the proposed study are to investigate how the criminalization of HIV non-disclosure shapes: 

  1. The gendered power dynamics of negotiating HIV disclosure, safer sex practices, and violence among WLWH
  2. HIV-related stigma and access to HIV treatment and care among WLWH

To do this, we will observe participants (e.g. in health care settings) and conduct in-depth individual interviews with WLWH, legal advisors, and health and social service providers.

There is potential to translate the findings of this research into evidence-based HIV policy that better considers gendered power dynamics and HIV-related stigma.

Implementation and ethical dimensions of scaling up HIV ‘Treatment as Prevention’: Examining the experiences of people who inject drugs

In 2010, BC launched the Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV) program, which implements antiretroviral Treatment as Prevention (TasP) through enhanced HIV testing and universal treatment for HIV-positive individuals. The success of TasP at the population level will be challenging. The needs for enhanced case-finding efforts, early treatment following HIV diagnoses, and consistent adherence to treatment regimes are among the top concerns, particularly with regard to a key target population for TasP: people who inject drugs (PWID).

This project will examine key implementation challenges and opportunities regarding PWID’s experiences with the testing, treatment and prevention imperatives of TasP policy and program delivery practices. The objectives are to:

  1. Collect and analyze interview accounts from PWID regarding their experiences with TasP
  2. Collect and analyze interview accounts of decision makers in order to characterize how various ethical and implementation considerations related to PWID are taken up or rejected
  3. Use the new information gathered to develop recommendations for tailoring TasP policies and program delivery practices to advance the effective and ethical scale-up of TasP among PWID

Optimizing anti-cancer peptides for use as novel cancer therapies

Anticancer peptides (ACPs) are small peptides (short chains of amino acids) that kill cancer cells by puncturing them or by triggering programmed cell suicide. In the lab, certain ACPs kill slow-growing and multidrug-resistant cancer cells, enhance action of anticancer drugs, and trigger the immune system to attack tumours. However, many also kill normal cells.

The goal of this work is to understand how the amino acid sequence contributes to selective cancer cell killing. This project will:

  1. Screen large numbers of ACPs to identify amino acids that maximize cancer cell selectivity
  2. Explore mechanisms of anti-tumour activity of our lead peptide Mastoparan

Peptide arrays allow hundreds of ACPs to be tested inexpensively. We will create many variant forms of the highly active ACP Mastoparan by substituting every amino acid in its chain with every other naturally occurring amino acid. A peptide array will be used to test which amino acids are vital for cancer cell killing and which ones harm normal cells.

Computer analysis will generate new ACP sequences with better predicted selectivity for cancer cells. The ACPs predicted to be most selective for cancer cells will be synthesized and screened, and the most promising ones will be tested for toxicity against human cancer cells and normal cells.

In addition, the immune system component of the anti-tumour activity of Mastoparan L will be explored further in vivo.

Ultimately, this project could give rise to peptides that selectively target cancer cells and induce an anti-tumour immune response.

Development of novel indolmycin derivatives for the treatment of MRSA

Since the discovery of antibiotics over 80 years ago, bacterial infections have been relatively straightforward to treat. However, the improper use of antibiotics has caused bacteria to develop antibiotic resistance, posing a serious global threat to preventing and treating common bacterial infections.

This project seeks to combat multi-drug resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) by improving on an antimicrobial compound that naturally occurs in the environment. Indolmycin is naturally produced by Streptomyces griseus and is active against multi-drug resistant MRSA strains.

We aim to develop forms of indolmycin that are more potent against MRSA by feeding Streptomyces griseus with variant amino acids. In addition, we will perform structure-based studies to elucidate the molecular mechanism of anti-MRSA activity in indolmycin. This will allow for rational design of more effective forms of indolmycin.

Ultimately, this research could give rise to novel antibiotics to treat infections such as MRSA that are developing resistance to our current toolkit.

Altered glutamate dynamics in a mouse model of Alzheimer’s disease: Novel early biomarkers with therapeutic potential

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

 

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. With no cure available, it imposes a major burden on society. In AD, a protein called amyloid beta accumulates into plaques in the brain. This event is an early and predictive marker for AD and can be detected up to 20 years before clinical symptoms arise.

 

We are exploring the dysfunction and hyperactivity of various cell types in the presence of amyloid plaques. We will investigate the possible role of altered glutamate dynamics in mouse models of AD. Fluorescent labelling will shed light on changes in glutamate signalling in awake and behaving AD mice. We will also test whether Ceftriaxone can restore normal glutamate dynamics in these mice.

 

Ultimately, our work with AD mouse models and novel glutamate imaging could shed light on possible drug targets and enable early intervention for people with Alzheimer’s disease.

End of Award Update

Source: CLEAR Foundation

 

What did we learn?

During our study it became clear that amyloid deposits have a drastic impact on glutamate signaling. This early cellular signaling deficit was only visible using in vivo 2-Photon imaging and a region-specific analysis of real time glutamate transients in direct proximity to amyloid plaques. We found areas of chronically high glutamate levels directly surrounding amyloid plaques and adjacent areas in which glutamate signaling was impaired. In larger scale wide-field real-time imaging experiments this effect was lost, indicating the importance of region-specific effects on cellular function in the early stages of the disease. Moreover, we used luminescent conjucated oligothiophens (provided by Dr. Peter Nilson, Linköping University) to visualize prefibrillary forms of amyloid. We found a direct overlap of these prefibrillary forms of amyloid surrounding the dense core plaque and a decrease in astrocytic GLT-1 transporter. We hypothesized that this decrease in GLT-1 is responsible for the observed glutamate dysfunction that was found in our experiments using stimulation experiments in awake and anesthetized animals. We thus used Ceftriaxone to restore GLT-1 expression in our mouse model of AD. We provided longitudinal imaging data of glutamate transients before and after Ceftriaxone treatment and could show that this partially restores glutamate signaling.

 

Why is this knowledge important?

As prefibrillary species are present in the brain before dense core plaques are formed it is important to further our understanding of their impact on cellular function. Moreover, it is essential to develop strategies that aim at the earlies stage that amyloids have on cellular function as these can be treated. Once neurons and other cells undergo cell death, strategies of recovery are much harder to implement. Our results provided a new therapeutical target that not only treats the disease on a symptomatic level but in an amyloid centric way that prevents/delays cellular dysfunction at an early stage in the disease.

 

What are the next steps?

We are currently expanding our research to investigate the impact of prefibrillary amyloid species on vessel function to search for more potential therapeutic targets.

 

Publications