The lack of effective antibiotics in cases such as surgeries, transplantations, early-term and complicated births, sepsis etc. could merely lead to death as antibiotics are crucially needed for treatment. Sepsis for instance, annually kills ~8 million people worldwide with almost 40% of all deaths are linked to antibiotic failure. Likewise, infections caused by bacterial biofilms represent ~65% of all clinical diseases, and there are no antibiotics to treat bacterial biofilms, specifically. Here, we propose using new synthetic and biosynthetic technologies to develop novel molecules alternative to antibiotics, particularly antimicrobial peptide-like compounds, to address a wide range of hard-to-treat bacterial infections.
Starting from our previously developed immunomodulatory and antibiofilm peptides, we aim to explore the structure-activity relationships of those peptides and biosynthetically design stable and highly active mimetics. We plan to use advanced animal models, synthetic and isolated human tissues (skin and lung tissues) for testing and addressing preclinical issues such as stabilities, formulations, toxicities, and optimal therapeutic dosing. If successful the proposed study will provide the first novel therapeutic strategy to tackle bacterial infections and these newly developed compounds would have a significant impact in treating diseases and preventing deaths.
As our population ages, an increasing number of Canadians experience difficulties with their vision. Although it is well known that both normal aging and age-related eye disease can affect a person's ability to see fine detail (such as in reading), tests of visual acuity used in regular eye examinations do not provide a complete picture of a person's ability to see in everyday situations, such as exercising and driving, where moving objects are often involved. Moreover, these tests often demand verbal instructions and do not accommodate sufficiently for the multilingual population of Canada with a range of cognitive functions. We propose to develop a technology utilizing eye movements to assess visual motion processing.
Our research will gather scientific evidence to understand the relationship between motion processing and eye movements in healthy seniors and patients with ophthalmic diseases, and whether it is practical to introduce the technology into clinical practice. This quick and non-verbal method of assessing vision provides a potentially cost-effective vision assessment strategy that addresses an important population health issue.
Retinal degenerative disorders are inherited diseases that affect tens of thousands of Canadians. The effects are devastating; severe vision loss or complete blindness occurs early in life, resulting in the loss of livelihood, mobility, and independence. There is no cure, and present treatments focus on easing the symptoms of blindness instead of preventing vision loss in the first place.
My research is focused on the prevention of vision loss by understanding how specialized structures in the light-sensing cells in the eye, called photoreceptor outer segments (OS), are made, and how defects in OS assembly result in photoreceptor death and blindness. Using genetically-modified frogs, I have replicated human disease caused by mutations in two genes, prominin-1 (prom1) and photoreceptor cadherin (prCAD). I have determined that these genes are necessary for OS organization, and am now working towards identifying their specific functions.
Identifying the roles of prom1 and prCAD will benefit scientists and patients. It will further our understanding of how OS are built, a topic of great interest to visual scientists, and aid in the identification of novel therapies for some of the most common human retinal degenerative disorders.
In our aging society, degenerative complications of chronic diseases are on the rise and account for a significant percentage of deaths. Among these, fibrosis is the most common, and yet no therapy capable of mitigating its effects is available. Investigating and understanding the signaling pathways that influence fibrogenic progenitor (FAP) fate will not only elucidate a key component of the regenerative process but may reveal pathways that could be targeted therapeutically to prevent inflammation, fibrosis, and enhance regeneration or maintain muscle homeostasis.
Here, we will focus on the ability of these progenitors to attract to damaged tissues specific inflammatory cells (eosinophils) that have been linked to fibrosis, with the goal of learning how to prevent their excessive accumulation and thus prevent this prevalent complication of muscular dystrophies and other chronic diseases.
Chronic diseases consume 67% of direct healthcare costs in Canada. Regenerative medicine (RM) is a powerful strategy to address chronic diseases. The next generation of RM therapeutics targets development of living cells and tissues to treat specific indications. Availability of stable progenitor stem cell bio-banks that can be differentiated to desired phenotypes is a crucial pre-requisite. My overarching goal is to understand how complex tissues emerge from pluripotent stem cells and use that knowledge to develop protocols to generate blood progenitor-forming tissues at clinical scales.
My approach rests on three complementary thrusts.
First, I will develop a computational model connecting the genetic code of the cells to their microenvironment to understand how interactions between the two govern cell fate.
Second, I will make pluripotent organoids to validate key parameters influencing earliest stages of stem-cell based blood development.
Finally, promising findings regarding parameters governing emergence of blood forming tissue will be tested in vitro via assays developed by the host lab, yielding pre-clinical data suitable for further technology development.
My work will reveal fundamental rules that govern the emergence of blood-forming tissues and generate new strategies for RM application. My computational approach will yield a new drug design & optimisation paradigm. The proposal will, thus, add to and reinforce BC's position as a leader in Regenerative Medicine.
The emergence of novel technologies in health care is associated with promising opportunities to improve patient health outcomes. Advances in health technologies also come at a substantial cost. New gene therapies have been estimated to cost between $300,000-$4,000,000 per patient. These new therapies offer promise, but do not offer certainty; decision-makers have to choose whether to reimburse the therapy with little evidence for how it might work in the real-world.
Health economics can be used to assess the value of a new therapy compared to current therapies. While the use of health economics seems to be supported, the extent to which it impacts decisions seems to be limited. The proposed research will improve health economics analyses to support decision-makers at BC Cancer. The approach will incorporate real-world evidence, expert and patient opinion, and effective communication with decision-makers. Chimeric antigen receptor T-cell (CAR-T) therapy will serve as a case study as it is promising, but is associated with high costs and uncertainty about long-term effectiveness.
This project will bridge the gap between the type of evidence that is provided by standard health economics analyses and that required by decision-makers.
Falls cause up to 80% of traumatic brain injuries (TBI) in older adults. Any fall from standing may cause TBI if head impact occurs. Humans use movement strategies to avoid head impact during falls, such as 'arresting' the fall with the arms. Through video capture of real-life falls, we found that these strategies persist but become less effective for older adults in long-term care, with over 1/3 of falls resulting in head impact in this setting. This project continues our work with Debbie Cheong (Osteofit Provincial Coordinator at BC Women's Health Centre) to design and evaluate novel exercise programs for enhancing protective responses for avoiding head impact in falls. We will identify the strength and flexibility demands of common safe landing strategies observed in falls in older adults, and design and evaluate feasible approaches to enhance those capacities for older adults of varying physical and cognitive status.
This project will lead to new evidence on the strategies that older adults use to avoid head impact during falls, and the musculoskeletal demands of those strategies; new exercise-based approaches for targeting and enhancing the effectiveness of fall protective responses in older adults; and evidence of the feasibility and effectiveness of our exercise program for older adults.
In scientific research, many decisions are needed. Some take scientific expertise, but others take knowing what people find important. Such 'value judgments' include: choosing a topic and how to study it, setting goals, and deciding how to share results.
Patients and the public can inform value judgments in research by being partners and sharing what is most important to them, including
- what is most important to know;
- what errors are most important to avoid.
This is necessary in health economics, the type of research that looks at health and costs as part of healthcare planning. This project will build on a study that asked health economists about value judgments, including whether and how value judgments in their studies could affect healthcare. In a new project, researchers will start a conversation with patients and the public about the same issue. First, they will create short videos about value judgments in research, including how health economists think about and manage them in their studies. Then, patients and the public who viewed the videos will be asked what they think. Could health economists do a better job of managing value judgments?
The study will help make sure health economics research in BC is clear, understandable, and done in partnership with patients and the public. It will help ensure that British Columbians' values are front and centre in research, including where to focus and how to manage possible errors in studies about healthcare.
Spinal cord injury (SCI) not just causes paralysis but also more devastating issues such as impaired blood pressure (BP) and heart rate regulation, which are among the leading causes of illness and death among this population. The individuals with SCI above the mid-thoracic level commonly suffer from highly labile BP that rapidly reaches alarmingly high and low levels within the same day. These extreme BP fluctuations often result in seizures, ruptured brain blood vessels and even death. Hence it is not surprising that the individuals with SCI rank improving heart and blood vessel function among the highest priorities for recovery, even higher than regaining the ability to walk again.
The goal of this proposal is to test the potential of non-invasive spinal cord stimulation (delivered through skin) to promote blood pressure control in a rat model of SCI. Our laboratory's pilot experiments have already demonstrated that non-invasive stimulation is feasible and effective in humans with SCI. Present proposal will allow us to thoroughly understand the underlying mechanisms and enable widespread clinical use of spinal cord stimulation in improving quality of life of individuals with SCI.
Over 400,000 Canadians live with long-term disability from stroke. Stroke survivors say regaining walking ability is a top priority; but, poor cognition, or thinking abilities, can limit walking in the community. How much walking recovery someone achieves likely stems from the brain's ability to dual-task (DT), like walking while talking. In fact, almost 80% of stroke survivors struggle with some aspect of cognition limiting full walking recovery after stroke. The complex demands of community mobility after stroke can be studied in laboratory settings using DT, where walking is done with a cognitive task.
Using DT, studies have found the brain is crucial for DT, and that altered levels of brain activity affect DT ability. But, little research probes if stroke survivors could produce brain recovery with DT training, as neuroimaging methods like functional MRI, cannot collect data during standing and walking. Functional near-infrared spectroscopy (fNIRS) is an ideal imaging tool to assess walking without physical limits, but its utility to detect if DT training can drive the brain to recover walking has not been tested in stroke survivors. So, the goal of our clinical trial is to test if DT training can help the brain recover and allow for better DT ability. DT training may drive brain recovery by addressing cognitive and motor difficulties at the same time, maximizing rehabilitation efforts, and improve walking ability in the community after stroke.
