Sepsis is a serious and life-threatening condition that arises from infections. Although medical advances have reduced the mortality rates of sepsis, many survivors have a weakened immune system and are at a higher risk for subsequent infections. Exercise represents a powerful tool to recover the immune system and reduce post-sepsis hospitalization. Through my research, I will explore how exercise impacts the immune system of sepsis survivors by specifically investigating immune cells called myeloid cells, which become dysfunctional following sepsis. Initial results in a mouse model of sepsis have found that four weeks of exercise improves survival to a subsequent lung infection due, in part, to restoration of immune system function and that female mice respond differently to sepsis than male mice. To understand this better, I will investigate how exercise changes immune cells and differences between sexes. In collaboration with an ongoing clinical trial in sepsis survivors, I will explore whether molecular changes in immune cells are present in human patients. Overall, my proposed research will lead to more effective exercise treatments for sepsis survivors to improve their quality of life and return back to health.
Research Location: Centre for Heart Lung Innovation
Characterizing the effects of cannabis smoking on airway epithelial cell reprogramming
Cannabis is the 2nd most used recreational drug in Canada, with 6 % of Canadians reporting daily use. Despite the known dangers of cigarette smoking to the lungs which involves exposure to inhaled toxins, smoking is the main method of cannabis consumption. The lungs are protected by a cell barrier called the airway epithelium that is damaged with cigarette smoking and can lead to lung disease. Whether this is true for cannabis smoking is unknown. In this study we aim to understand if cannabis smoking damages the airway epithelium and whether it can be reversed. Epithelial cells collected from cannabis smokers will be analyzed to identify any changes that indicate harm to cells. We believe cannabis smoking is toxic to epithelial cells, reducing the protective ability of the airway epithelium and ultimately leading to worse lung outcomes. This damage may be reversed by stopping cannabis smoking, which would restore epithelial cells back to health. Study findings will be presented at international conferences, published in leading journals and importantly, shared with students using in-school initiatives. This work will build on our understanding of how cannabis smoking affects the lungs and may change how people use cannabis.
Innate immune mechanisms of viral myocarditis: Role of the cytosolic DNA-sensing pathway
Coxsackie virus B (CVB) is the number one cause of viral heart inflammation leading to heart failure and sudden death in ~20 percent of infected children and young adults. In most people, CVB infection causes mild symptoms. However, individuals with underdeveloped and/or compromised immune systems are at increased risk of severe disease. Normally, our healthy immune system acts as a first line of defense against viruses, but excessive and sustained activation of our immune system can be harmful, leading to chronic inflammation and injuries to the heart. The objective of my project is to study how CVB hijacks a novel immune pathway called cGAS-STING, to trigger harmful inflammation in the heart. Our knowledge gap is that we do not completely understand how CVB hijacks the cGAS-STING immune pathway and whether blocking this pathway with drugs can protect the heart. To accomplish this goal, we will precisely identify which cells and immune pathways are responsible for harmful inflammation of the heart. Findings from this study have the potential to open new therapeutic avenues to combat existing and emerging viral threats.
Dissecting heterogeneity in COPD: A functional imaging-guided-omics study
Chronic obstructive pulmonary disease (COPD) is a common lung condition with no known cure. Understanding lung abnormalities in COPD is critical to develop new treatments. However, lung abnormalities in COPD are ‘patchy’, and test samples (e.g. biopsies) used for laboratory studies may not be from the most diseased areas. We will use advanced lung imaging techniques (magnetic resonance imaging (MRI) and computed tomography (CT)) to identify ‘high-disease’ areas in the lungs of volunteers with COPD, and take samples from these areas using a camera inside the lungs (bronchoscopy). We will take samples before and after treatment with a common antibiotic medication (azithromycin) and test for changes in lung genes. Our approach may ultimately help develop new treatments for the 384 million people worldwide who suffer from COPD.
Air pollution as a modulator of molecular, structural, and clinical outcomes in patients with fibrotic interstitial lung disease
Interstitial lung diseases (ILDs) are serious conditions resulting in lung scarring, breathing difficulties, and a severely shortened lifespan. Air pollution is associated with ILD development and progression, but we do not understand why. This project aims to answer this question by looking at cellular and genetic changes that occur in the lungs of patients with ILD following exposure to air pollution. Using satellite-derived air pollution and clinical data from patients, we will determine if certain genes result in worse clinical outcomes when patients with ILD are exposed to more air pollution. Next, we will examine how air pollution modifies how genes are turned on or off in ILDs, through a process called DNA methylation. Lastly, we will use high-resolution imaging tools to understand how the structure of the lungs change in response to air pollution in patients with ILD. This research will help us to understand how air pollution contributes to progressive lung scarring in patients with ILD and may identify new targets for therapies to reverse lung scarring. This work will inform environmental health policies aimed at protecting vulnerable populations, including patients with ILD and other chronic lung diseases.
Cholesteryl ester transfer protein-mediated regulation of HDL cholesterol levels and clinical outcomes in sepsis
Sepsis is the overwhelming immune system response that occurs when someone develops a serious infection, and is responsible for one-fifth of all deaths worldwide. Sepsis occurs when the immune system becomes over-activated by lipid components present in bacteria, and ultimately leads to dysfunction of critical organs and death. These bacterial lipids (called pathogen-associated lipids or ‘PALs’) are transported through the bloodstream by lipoproteins, the same “vehicles” that are used for cholesterol transport. Among these vehicles, high density lipoprotein (HDL) plays a central role transporting PALs. However, HDL levels significantly decrease during sepsis, leading to reduced clearance of PALs. In our previous work, we discovered that inhibiting a specific gene called cholesteryl ester transfer protein or CETP preserved HDL levels during sepsis, suggesting that this may be a new approach to treat sepsis. We now aim to study the mechanism by which CETP regulates HDL to combat bacteria, and whether CETP inhibition will improve mouse survival in a clinically-relevant sepsis model. Completion of this project will provide new insights into the therapeutic role of CETP inhibitor in sepsis, ultimately improving the health of Canadians.
The association of genetic risk factors with morphology and outcomes in interstitial lung disease
Interstitial lung disease (ILD) is a diverse group of illnesses with a variety of causes. The current approach to diagnosing ILD depends on the specific patterns observed on imaging studies (CT scan) and lung biopsy. There is increasing evidence that an individual’s genetics play a complex and important role in determining disease behaviour across different ILD subtypes. This study will examine whether common genetic risk factors predispose patients to different forms of ILD, influence treatment response, and predict prognosis. Investigating these genetic risk factors will improve our understanding of the biology that drives ILD and will help to develop a better system for ILD classification and diagnosis.
Targeting efferocytosis to reduce risk of cardiovascular events
Heart attack and stroke are the leading causes of death in Canada. These lethal events are caused by diseased cells accumulated on the wall of the blood vessels, leading to narrowing of the arteries. Although diseased cells can be removed naturally, this process is inhibited by inflammation. Recently, anti-inflammatory drugs are being actively developed to reduce heart attacks, but we lack methods to assess their effectiveness before testing in patients. This problem led to the failure of several clinical trials and serious side effects due to non-specific inhibition of the immune system. We will use models that closely mimic the conditions of patients and apply a thorough “onsite inventory” of diseased arteries to: 1) understand how inflammation inhibits the removal of diseased cells; 2) see if current drug candidates can neutralize these adverse effects in diseased arteries; and 3) explore and develop markers that can find patients who will benefit from the drug candidates. This study will provide evidence to guide the design of more specific anti-inflammatory drugs and their application to the right patients. It will minimize side effects and allow more patients to be properly treated to prevent heart attacks and strokes.
Valvular heart disease and bioprosthetic heart valves: Defining mechanisms of degeneration and therapeutic discovery from bedside to bench
Aortic stenosis (AS) is a narrowing of the valve that controls blood flow from the heart to the body. AS results in significant decline in quality of life and can be fatal if untreated. Unlike most types of heart disease, there is no medication to treat AS and the primary therapy option is replacing the diseased valve with an artificial one by open-heart surgery or transcatheter implantation (insertion of an artificial valve through the blood vessels leading to the heart). Unfortunately, artificial valves can be dysfunctional and have limited durability, which can lead to heart failure, the need for repeat valve replacement, or death. With a focus on clot that can form on artificial valves, this research aims to determine the causes of valve dysfunction and degeneration, define methods to detect and predict which patients will experience valve dysfunction, and identify methods to increase valve durability. Overall, this work will provide critical new information to guide clinical care and the future evolution of artificial heart valve use that will improve the outcomes and quality of life of patients with AS.
Investigating sex differences in dyspnea across the spectrum of chronic obstructive pulmonary disease severity
Chronic obstructive pulmonary disease (COPD) results in breathlessness, reduced activity level and quality of life. The number of women with COPD in BC is increasing. Healthy women experience more breathlessness during exercise compared to men. Women with mild COPD experience even more breathlessness and report worse quality of life. The basis for sex differences in breathlessness across the full spectrum of COPD disease severity has not been studied and is the main focus of our proposed research.
We will explore how breathlessness differs between women and men with mild-to-severe COPD in a group of patients that undergo lung function testing and specialized exercise testing as well as using data from a Canadian cohort study of COPD patients. We will also use high resolution imaging of the lungs to relate structural changes due to COPD to the symptoms women experience.
This is the first study to explore sex differences in breathlessness across COPD disease severity from two perspectives, using detailed exercise tests and a complementary COPD database. Understanding breathlessness in women with COPD is a first step in order to develop effective treatment strategies for the increased symptoms women experience.