Redefining atherosclerosis: Characterizing and targeting smooth muscle cell foam cells for the treatment and prevention of coronary heart disease and stroke

Heart attack, heart failure, and stroke are major causes of disability and death in BC and worldwide. The main cause of these conditions is the buildup of blockages or "plaque" in arteries in a process called atherosclerosis. For a long time, it was thought that the main place where fats (like cholesterol) build up in plaque are white blood cells called macrophages, but our laboratory made the novel discovery that it is actually smooth muscle cells (SMCs) in arteries that are most prone to becoming cholesterol-overloaded, which has important implications on developing ways to prevent heart attack and stroke.

We now propose to perform an in-depth characterization of SMCs to understand how they become overloaded with cholesterol. In addition, we will determine whether differences in SMC gene expression protect some people from plaque formation, how cholesterol-overloaded SMCs in human hearts respond to cholesterol-lowering medications, and whether turning on a particular gene in SMCs can prevent them from forming plaque and remove excess cholesterol from SMCs after it has been deposited. This work will provide vital new knowledge to reduce the burden of heart attack, stroke and heart failure in BC and beyond.

Treatment of Pediatric Mental Health Problems: Unravelling the Role of Patient and Family Motivation in Eating Disorder Outcomes

My goal is to improve treatment for children and youth with eating disorders (ages 8-24 years). Eating disorders typically develop during adolescence. Eating disorders can become lifelong, and cause permanent health problems and even death. Making sure that each child gets the right kind of treatment can lead to the best outcomes. But, current guidelines do not consider how to match a child to the best type of treatment.

Knowing about motivation to change in children and families can help clinicians match a child to the best treatment. People who are motivated to change recognize there is a problem and are willing to work on this problem. Higher motivation leads to better eating disorder treatment outcomes in adults. Yet, motivation is not well-studied in youth. In fact, youth are often brought to treatment by their parents. So, parents’ motivation to help their child may be one of the most important features to measure.  

This project will tell us how youth and family motivation affect eating disorder outcomes. It will also tell us how clinicians use information about motivation. At the end of the project, I will be able to update guidelines about how to match a child to the best treatment.

Novel metabolomics approach for the diagnosis of infectious diseases

Tests to determine whether an individual has a disease or not are often expensive and performed on complex instruments in laboratories. As such, there is currently an important unmet need for tests to diagnose infectious diseases with highly accurate, inexpensive and simple methods that could be performed nearer to the patient.

We have developed a method that can identify the metabolites (small molecules) that change in response to infection. As a proof-of-concept, we demonstrated its successful use for the highly accurate detection of respiratory viruses directly from swabs taken from the nasopharynx (upper part of the throat behind the nose).

We now aim to expand this method to a new testing instrument at the BC Centre for Disease Control and assess its test performance for the detection of other infectious diseases like human papillomavirus (HPV) and tuberculosis (TB). Identification of a limited set of metabolites for each condition will enable the adaptation of the method to a simpler, near-patient diagnostic test. Such a test has the potential to reduce the time it takes to obtain an accurate diagnosis and improve clinical outcomes at a population level.

Development and evaluation of a novel wearable gait analysis tool for remote monitoring and assessment of patients with musculoskeletal injuries

Regular physical activity is known to produce significant physical and mental health benefits, yet only 15% of Canadian adults meet the recommended guidelines. Running is one of the most popular leisure-time physical activities and is effective even in low doses. However, runners sustain a high rate of musculoskeletal injury, with up to 50% suffering an injury annually. Many injuries are due to abnormal running form. The emergence of wearable technology has presented an opportunity not only to collect information on running form outside of a research lab setting, but also remotely. This project aims to develop and evaluate an innovative remote gait assessment system using wearable technology that will allow clinicians to measure, monitor, and reassess patients with gait impairments remotely. This tool has the potential for physiotherapists to assess running injuries clinically in a way that currently is only possible in research settings. The development of a clinical assessment tool to objectively measure running gait outside of a lab is an exciting opportunity especially as COVID-19 is reshaping the way health care is delivered and increasing telehealth options for clinicians to work remotely.

Cost-effective biomarker driven treatment for chronic lymphocytic leukemia in the era of precision medicine

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Ibrutinib, a new drug that works differently from chemotherapy, is a major breakthrough for CLL treatment and allows patients to live longer; however, it comes at a high cost to the BC health system.

Objective

  • Our goal is to determine which patients benefit most from ibrutinib at what point in their disease, so that ibrutinib, and other drugs like it, are given to the right patients at the right time and avoided in those who will only suffer side effects.

Methods

  • We will analyze the impact of ibrutinib on the BC CLL population including patterns of use, side effects and survival. We will perform genomic testing on samples from CLL patients on ibrutinib to find gene mutations that develop over time that may help predict who will respond well. Finally, we will combine this information to determine the overall cost of ibrutinib to the BC population, particularly when treatment is targeted to those who will benefit most.

Impact

  • This approach is crucial to ensure ibrutinib is affordable for healthcare systems and accessible for all those who need it, ultimately leading to improved quality of life and survival of CLL patients.

Motor vehicle crash risk after cardioverter-defibrillator implantation: A population-based evaluation

Motor vehicle crashes result in 78 million injuries worldwide each year. Some crashes might be prevented by restricting driving for individuals with medical conditions that might cause sudden incapacitation while diving (eg. epilepsy, sleep apnea).

About 4,000 Canadians will have an implantable cardiac defibrillator (ICD) implanted this year. ICDs treat life-threatening cardiac rhythm abnormalities and prevent cardiac arrest. A heart rhythm problem or device malfunction in the weeks after implantation might result in a crash, so patients are warned not to drive for 4 weeks after ICD implantation.

Do driving restrictions after ICD implantation prevent crashes? Would driving restrictions be more effective if they were modified? The answers to these questions aren't known.

British Columbia's health and driving databases provide a unique opportunity to examine crash risk after ICD implantation. The MVC-ICD study will use health and driving records to compare crash risk among 9,000 ICD patients to crash risk among control patients. Results will provide an immediate opportunity to improve clinical practice, licensing policy and road safety in Canada and abroad.

Implementing quality indicators through clinician and patient online toolkits to improve rehabilitation care and outcomes after hip and knee replacement for osteoarthritis

Each year, more than 18,000 British Columbians have joint replacement surgery for hip or knee osteoarthritis. Many face challenges in getting timely, quality rehabilitation before, and especially after surgery. I have developed quality indicators that set minimum standards of rehabilitation care for joint replacements. Focusing on 10 of these quality indicators for care after surgery, my team of clinicians, patients and researchers have created online toolkits to help make these indicators available to patients and clinicians who provide joint replacement rehabilitation in BC. The toolkits contain resources such as checklists, videos, and posters. After first testing our study procedures, I will run a study to see if the toolkits make a difference in overall quality of rehabilitation care and lead to better experiences and results for patients. Patients, clinicians and those who make decisions about healthcare services, will be part of every stage of this work. I will share my findings widely to researchers, clinicians and patients locally and across Canada. This research will lead to better, more consistent care for patients and improve the joint replacement rehabilitation services available in BC.

Delineating the pathophysiology of hypoxic ischemic brain injury after cardiac arrest to identify therapeutic targets

The main determinant of patient outcome following revival from cardiac arrest (heart stops pumping blood and oxygen to the body) is the brain injury that occurs in the days after hospital admission. This injury, termed hypoxic ischemic brain injury, partly arises from a lack of oxygen delivery to the brain after resuscitation. The cornerstone of post-cardiac arrest management has involved increasing the delivery of oxygen to the brain to facilitate recovery.  This logic assumes that the transport of oxygen from the blood system into the brain tissue is normal after cardiac arrest. I have recently demonstrated that this assumption is not true and in fact, in a large proportion of post-cardiac arrest patients demonstrate an inability to unload oxygen into the brain from the blood vessels. The mechanisms explaining this observation are unclear and not accounted by tests including CT and MRI scans. Therefore, another approach is required.

My project involves using a series of novel blood tests that arise from structures in the brain that are responsible for oxygen transfer. Identifying the precise structures that inhibit oxygen delivery into the brain will lead to further research aimed at identifying therapeutic targets.

A patient-oriented mental health recovery effort: Working across sectors to alleviate suffering related to burnout, post-traumatic stress disorder, or treatment resistant depression

The mental health of healthcare providers is understudied and inadequately supported, especially given the current pandemic. Workplace stress can lead to burnout, Post-Traumatic Stress Disorder (PTSD), and Treatment Resistant Depression (TRD), which affects morale, absenteeism, retention, and patient care. The focus of this application is to address PTSD and TRD with a combination therapy involving Roots to Thrive (RTT) Communities of Practice (CoP) with Ketamine-Assisted Psychotherapy (KAP). The RTT CoP have documented enhanced efficacy for resilience, mental wellness and cognition. Ketamine is described as the single most important advancement in the treatment of depression in over 50 years.

My program of research innovatively examines the synergy of these two interventions, an evidence-based treatment known as RTT CoP-KAP. My research aims to lead the development and implementation of a more inclusive mental health model that continues to prescribe connection to self, spirit, and community as the primary healing modality, and further supporting with medicine-assisted healing modalities (beginning with ketamine and then expanding to include MDMA).

Moving towards a biology-based care model in germ cell tumors

Testicular germ cell tumors (GCTs) are the most frequent solid tumors in young men. Chemotherapy can cure most patients even when the tumor is advanced. However, there are still two main issues of concern.

  1. Survivors have an increased risk of developing other diseases (e.g. heart disease, new tumors, strokes, etc.) as results of the late side effects of chemo- and radiation- therapies.
  2. Current methods to detect GCTs rely on a CT scan and blood work for tumor markers which are not specific enough for GCTs. This means there are patients who are falsely considered as having the tumor and more importantly, being treated unnecessarily with chemotherapy, radiation or surgery.

Our research program aims to reduce this uncertainty by analyzing some small RNA fragments (micro-RNAs) in the blood of GCTs patients that are produced only by the GCTs cells. Although several small studies have demonstrated those micro-RNAs are better than the CT scan and serum tumor markers to detect GCTs, we still need to validate this test in a larger number of patients before it can routinely be used in clinical practice. We have therefore designed two clinical trials to validate the clinical utility of micro-RNAs in the management of GCTs.