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.

The effects of 60% oxygen during exercise training in patients with fibrotic interstitial lung disease

Breathing discomfort is common in patients with interstitial lung disease (ILD) and often results in an inability to perform physical activity, leading to a poor quality of life. Exercise training can reduce breathing discomfort and enable ILD patients to perform physical activity. However, severe breathing discomfort makes it challenging for these patients to withstand the amount of training they need to get the most benefit. A recent study showed that ILD patients breathing supplemental oxygen had less breathing discomfort and were able to exercise for longer compared to breathing room air. Another study showed that breathing supplemental oxygen was safe for patients with ILD for a single exercise session. However, we still do not know if these findings can be applied to a long-term exercise program.

Therefore, the purpose of this study is to determine if using a higher amount of oxygen during a rehabilitation program is a safe intervention that translates to greater benefits from training compared to the same regimen without the additional oxygen. We are also interested in examining if higher intensity training sessions with added oxygen affects every day physical activity levels.

Assessing Small Airway Disease Heterogeneity in Asthma to Identify Novel Therapeutic Targets

Asthma is a serious public health issue in Canada and in the world, affecting more than 300 million people globally. To date, clinical trials have established that current treatment strategies for asthma can relieve patient symptoms, but none are able to reverse the disease process. It is known that in asthmatic lungs, the airways -tubes that allow air to flow in and out of the lungs for breathing – are continually injured and scarred in a process called fibrosis. The smallest airways in the asthmatic lung are the main sites of fibrosis and thought to have the greatest contribution to disease symptoms; however, current methods used to assess asthma are unable to provide information on the smallest airways.

Assessing these smaller airways could provide new ways to develop drugs to resolve the scarring that occurs in asthma. In this project, we will use new, more powerful imaging methods to determine the contribution of the small airways scarring in asthma and to identify the genes involved in this process. We will then develop laboratory models of the disease using patient lung cells that may be used in the future to develop new drugs to target the genes involved and resolve the scarring and blockade in the airways of asthmatic patients. The potential new drugs that will be found in this research will help to relieve the burden of asthma in BC.

 

HEARTBiT: A novel multi-marker blood test for management of acute cardiac allograft rejection

Patients receive heart transplants as a life-saving measure after heart failure; thus, ensuring the success of the transplant is of utmost importance. Rejection is a primary cause for heart transplant failure, and consequently, heart transplants are monitored at least 12 to 15 times within the first year of operation. However, current monitoring requires biopsies, a surgical procedure which requires repeated sampling of the heart muscle. This procedure is invasive, expensive, and stressful to patients. Replacing the biopsy with a simple blood test can greatly improve patient quality of care and reduce healthcare costs.

Therefore, my goal is to develop a new blood test to monitor rejection following heart transplants. Using sophisticated computer algorithms, our group discovered molecules in the blood that can discriminate between patients who have rejected their heart transplants and those who have not. My goal is to develop a blood test to precisely measure these molecules. Also, I will study these molecules for their biological role in heart rejection process by examining immune cells and damaged heart cells found in biopsies. Accomplishing these research goals will produce a valuable clinical tool that can diagnose rejection in a fast, accurate, cost-effective, and minimally invasive manner.

Improving sepsis outcomes with anti-PCSK9 monoclonal antibody therapy

Sepsis is a severe disorder that occurs when human defense cells fight off an infection in an uncontrolled manner that can cause organ damage and death. Unfortunately, there is no specific treatment for sepsis, and there is a limited understanding of the mechanisms driving this deadly disorder.

During infection, toxins are released in the blood and carried inside cholesterol particles, which are removed from the blood by the liver. People with decreased levels of PCSK9 (proprotein convertase subtilisin/kexin type 9), a protein that normally regulates cholesterol particle levels, seem to have an increased ability to clear toxins from their blood. This project aims to test if inhibiting PCSK9 increases the removal of toxins from blood during sepsis and reduces organ damage and mortality. The findings of this research can lead to improved understanding and management of sepsis, and potentially a new treatment for sepsis that could save thousands of lives every year in the future.

Targeting the complement system in Alzheimer’s disease

Many seniors aged 65 or older experience “age-associated memory impairment,” a normal aging process. However, Alzheimer’s disease is different, and not a normal part of aging. Alzheimer’s is a progressive brain disease with gradual loss of nerve cells and resulting problems with thinking, memory, and movement. Changes in the brain can start to happen 20 years before any memory problems appear.

Currently, no treatments are available to cure Alzheimer’s disease; however, if the disease is diagnosed and treated at an early stage, patients have a greatly improved quality of life.

Measurement of some proteins in a body fluid found in the brain and spinal cord has been used to aid in diagnosis. The sample collection is performed by inserting a needle into the spinal canal. People are usually reluctant to take the test, which causes a delay in diagnosis.

Dr. Shi’s research aims to develop a new test that could help doctors diagnose Alzheimer’s disease at an early stage. This new test is different from the current tests in two ways in that it uses blood instead of spinal fluid, which is much easier to get through venipuncture; and uses a new technique that is more sensitive and specific.

The resulting blood test could be a convenient and accurate way of diagnosing Alzheimer’s disease at an early stage.

Structural valve degeneration in bioprosthetic heart valves

Bioprosthetic heart valves (BPHVs), valves made of biologic tissues rather than synthetic materials, have revolutionized the treatment of heart valve disease, which constitutes a significant health and economic burden in BC, Canada and around the world. BPHVs serve as an alternative to mechanical valves, which require lifelong treatment to prevent clotting and therefore lead to an increased risk of bleeding.

 

With the development of new transcatheter methods for delivery of BPHVs, they now represent the overwhelming majority of valves. Despite these successes, the long-term durability of BPHVs is not well established and remains a concerning potential limitation.

 

Dr. Sellers’ research will look to determine how BPHVs degenerate and potential strategies to assess this in patients. This will include using a combination of analysis of dysfunctional valves and novel imaging approaches using computed tomography (CT) imaging.

 

The results of this research will help determine the long-term durability of BPHVs and improve decision-making for patients with heart valve disease.

 


End of Award Update – July 2022

Most exciting outputs

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 only option is replacing the diseased valve with an artificial / bioprosthetic valve. Unfortunately, bioprosthetic valves have limited durability and degenerate, which can lead to heart failure, need for risky repeat valve replacement, or death.

The work proposed and completed during my project aimed to define and characterize the processes in bioprosthetic valve degeneration as well as evaluate novel imaging methods to detect and predict degeneration of bioprosthetic valves. Key findings of this work demonstrate our progress in these goals.

Specifically, we were able to extensively characterize degeneration in a number of cohorts of failed/explanted valves:

Further, it is exciting too that we were also able to link these processes of degeneration to clinical imaging approaches to improve detection and valve pathology and prediction of degeneration:

This work would not have been possible without the support of my partnered Research Trainee award from Health Research BC, the Centre for Heart Lung Innovation, Providence Research, and St. Paul’s Foundation.

 

Impacts so far
Overall, my Research Trainee award was critical to enabling my research. During the duration of the award, I was able to make many steps forward towards the ultimate goal of extending the life span of artificial valves and improving outcomes and quality of life of patients with valve replacements. My current research findings to date have provided novel fundamental and translational scientific insights into the processes of bioprosthetic heart valve degeneration, including establishing a timeline and clinical associations with degeneration and evolving our understanding of new techniques for detecting valve degeneration. Ultimately, these are critical steps in developing the science needed for the future evolution of artificial heart valve design, use and patient care.

 

Potential future influence
The research conducted during this award has formed the basis of my research program as a new investigator at the Centre for Heart Lung Innovation. This work is the foundation for on-going basic and translational science laboratory investigations and is also linked with some of our on-going clinical studies.

 

Next steps
I’ve had the exciting opportunity to continue my work through my position as a Translational Research Scientist at Providence Health Care and as an Assistant Professor in the UBC Division of Cardiology / Department of Medicine where I work as an investigator at the Centre for Heart Lung Innovation based at St. Paul’s Hospital, a University of British Columbia teaching hospital. In this role, my laboratory, the ‘Cardiovascular Translational Lab’, continues to investigate preventing and treating valvular heart disease with a primary focus on valve replacement with bioprosthetic valves. As part of this we host all-welcome translational research seminars, ‘hands-on’ valves teaching sessions for diverse groups of learners and those impacted by heart valve disease, and participate in local and international conferences.

 

Useful links

Integrative genomics to identify novel therapeutics and biomarkers for COPD

Chronic obstructive pulmonary disease (COPD) affects 300 million people worldwide and is the third leading cause of death, responsible for over 3 million deaths per year. It is the number one reason why adults end up in hospitals. However, we do not have good drugs to treat patients with COPD. This is because we do not fully understand how and why COPD develops and progresses.

Smoking can cause COPD but not all smokers get the disease; our genes also play a role. Identifying which genes cause some people to get COPD or lead to disease worsening over time will allow us to understand these processes more and to develop new drugs to treat the disease.

This project will use sophisticated analysis tools called integrative genomics. First, we will identify regions of our DNA that are important for COPD risk and worsening over time. This will be done through studying DNA regions from thousands of subjects with and without the disease and on whom we have information on how well their lungs work. We will then identify the function of these DNA regions by uncovering their effect on gene products and proteins in tissues that are important and relevant for COPD such as lung and blood. These genes and their products will be tested in laboratories to confirm the findings. The goal is to use this information to monitor disease and will additionally allow us to interfere with these gene products to treat disease.

IgE-mediated inflammation generated by the airway epithelium is antigen independent: A cause of a novel asthma phenotype

Asthma is the most common chronic disease in childhood and continues to increase through adulthood. When a patient has asthma, airways in the lungs become swollen and tight causing symptoms such as shortness of breath, wheezing, chest tightness, and cough. Current therapies for asthma relieve symptoms but do not restore airways back to normal function or cure the disease. 

Asthma is influenced by many different genetic and environmental factors, so despite having many drugs available and more in development it is extremely difficult to match patients to the right treatment. To better match patients to the right therapies we need to understand the process by which allergies lead to asthma. 

This project aims to find new ways to predict the response of asthmatic patients to existing and new drugs by better understanding how allergies cause asthma symptoms. We will look at several molecules in the blood known to be important in asthma, and measure them in airway tissues and cells obtained from asthmatic and non-asthmatic patients. This will give us a much better picture of what these important molecules are doing directly at the source of the allergic inflammation.

The role of PCSK9 in clearance of bacterial lipids and the development of anti-PCSK9 treatment for sepsis

Sepsis, which is characterized as an uncontrolled inflammatory response to severe infection, is the leading cause of death in intensive care units. In Canada, sepsis led to a total of 13,500 deaths in 2011, which translates to approximately one in 18 deaths in Canada involving sepsis. Despite this pressing medical need, there are currently no effective treatments for sepsis. 

It is well established that bacterial lipids, such as lipopolysaccharide (LPS) in Gram-negative bacteria and lipoteichoic acid (LTA) in Gram-positive bacteria, induce aberrant inflammatory response in sepsis and they associate with various lipoprotein fractions in the blood. Recent research has revealed that septic patients with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) loss-of-function mutations have better survival rates due to increased bacterial lipid clearance. It is likely that inhibition of PCSK9 leads to enhanced clearance of bacterial lipids and thus an improved chance of survival. 

Dr. Leung will characterize the role of PCSK9 in these two major pathways of bacterial lipid clearance by utilizing a novel in vivo imager to monitor the distribution of fluorescently-tagged LPS and LTA in mice. He will assess the therapeutic potential of PCKS9 inhibition by examining the ability of anti-PCSK9 monoclonal antibodies to clear bacterial lipid-laden LDL and VLDL through the LDLR and VLDLR pathways, respectively. 

Dr. Leung’s research will address a current knowledge gap in the role of lipoprotein pathways in the clearance of inflammatory bacterial lipids from circulation.