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.

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.

Quantitative Isotype Profiling And Dynamics Of SARS-CoV-2 Infections: Next-Generation Serology

We are making a blood test that will tell us a lot of information about the body’s response to the COVID-19, including whether a person is likely to get really sick or will easily fight off the virus. The blood test is will be easy to take, using only a drop of blood from the tip of the finger. The test is run using cutting-edge technology so that we can test a lot of people, at low cost, while getting the right results. The test will help prevent people from getting severely sick from COVID-19 by letting doctors know BEFORE things get worse that their patient may need additional care to help fight off the virus. For our citizens most at risk, like the elderly and those with other medical conditions, the results can be used to direct resources and support where they are needed most.