Cardiovascular disease (CVD) is the leading cause of death of Canadians, and is strongly influenced by genetic factors. Integrating basic biomedical research into how specific gene variants influence the function of cardiac cells, with clinical research of patients and families with early onset CVD, will lead to important advances in translating the results of genetics research to improved care for patients and families with CVD.
Research Location: Centre for Heart Lung Innovation
Understanding the aging HIV lung from dysbiosis to cell injury
Patients with human immunodeficiency virus (HIV) are now living to older ages thanks to effective anti-HIV medicines. Despite these gains, many of them suffer from chronic lung disease that greatly impacts their ability to carry out their daily activities and impairs their quality of life. The type of lung disease they face is similar to what longtime smokers develop, a progressive narrowing of the airways and destruction of the lung. However, in HIV, the process appears to be accelerated and more severe. It’s not unusual, for instance, to see patients in their 30s and 40s develop this lung disease (which is approximately 30-40 years earlier than expected). Also, it’s not unusual for HIV patients who have never smoked before to develop this kind of disease. Unfortunately, the traditional medications we use to treat lung disease often interact with anti-HIV medicines, causing severe side effects. Management of breathing symptoms in HIV patients is therefore difficult and it is imperative that we find better agents to combat lung disease in this population. Only by understanding what causes and drives this lung injury process can this goal be achieved, though.
Multiple studies have now shown that smoking alone cannot explain the lung disease phenomenon in HIV. I believe that HIV injures the lung in a two phase process. First, the virus directly breaks down the protective layer of the airway known as the epithelium. Second, over time, as patients develop repeated lung infections due to their weakened immune systems, the bacterial community of the lung or microbiome shifts. I believe that this community disruption results in molecular changes that age the lung faster. My approach is to perform an in-depth investigation into the epithelium of the airway using two innovative methods. To explore the injury that HIV inflicts on the airway, I have created a novel model of the HIV airway using HIV-infected cells co-cultured on a cell culture model of the airway epithelium. We will use this model to see how HIV-infected cells break down the protective barrier of the lung. To explore the shifts in the microbiome, I have collected airway cells from HIV-infected and uninfected patients to not just describe what bacteria exist in the airway but also to determine what effect the community differences between the two groups have on the function of genes in the cells. We will measure how ‘old’ these cells are and compare these findings to uninfected patients.
End of Award Update: December 2022
Most exciting outputs
The work of my laboratory was the first to detect accelerated epigenetic aging and methylation disruptions in the HIV airway epithelium, work that has now been published in the American Journal of Respiratory and Critical Care Medicine, and eBioMedicine.
Impacts so far
These insights into accelerated aging in the HIV airway epithelium provide clues into why people living with HIV may be prone to developing chronic lung diseases such as Chronic Obstructive Pulmonary Disease or COPD.
Potential future influence
Our work highlights the importance of accelerated aging in HIV, even in patients with well controlled infection. Reversing these aging mechanisms may be critical in the prevention or attenuation of airflow obstruction in this population.
Next steps
We are continuing to explore mechanisms of early aging in the HIV airway using novel technologies such as magnetic resonance imaging, optical coherence tomography, and single cell sequencing.
Useful links
- The relationship between the epigenetic aging biomarker “grimage” and lung function in both the airway and blood of people living with HIV: An observational cohort study (eBioMedicine, August 2022)
- Airway Aging and Methylation Disruptions in HIV-associated Chronic Obstructive Pulmonary Disease (American Journal of Respiratory and Critical Care Medicine, April 2022)
Developing personalized anti-arrhythmic drug therapy for atrial fibrillation
Atrial fibrillation (AF) is the most common heart rhythm disorder. With an aging population, the number of people with AF is expected to rise dramatically. People with AF are twice as likely to die, are five times more likely to have a stroke, can develop worsening heart muscle function, and have a lower quality of life. We have learned that a person's genetic makeup, or DNA, has a major impact on their risk of developing AF; but we have a limited understanding of why, or how to use this information to treat people in a safer and more effective way. People with AF first receive drugs to control their irregular heart rhythm. Even people who have procedures to treat AF are also prescribed drugs. This is particularly important in the group of patients who have persistent AF, who require electrical or chemical therapy to change their heart rhythm, as the success of surgical procedures in this population is well below 50%. Unfortunately our current drugs are generally ineffective, and can be unsafe, with little progress in drug development over the last two decades.
With these challenges in mind, the first goal of my research program is to identify and understand the genes that play a role in the development and progression of AF, and determine which are most common and most important in the Canadian population. To do this, I am gathering a biobank of AF patients and performing the largest scale detailed genetic testing in this population to date. I am also focused on understanding the effect that genes can have on the safety and efficacy of rhythm controlling drugs, and have already started a trial, funded by the Canadian Cardiovascular Society, that will link a person's genetic makeup to these important outcomes. I will then be able to take this large clinical and genetic data set to the laboratory where we have developed the unique ability to generate patient-specific stem cell disease models of AF. The ultimate goal of my research program is to directly tailor therapy for AF patients based on their genetic makeup, using information from clinical research and personalized disease modeling.