Up to two percent of patients will experience a stroke during or after surgery and these patients have a high chance of disability and death. Currently, we don’t understand clearly how to prevent, detect, and treat stroke after surgery. Although risk factors have been identified including older age and cardiac surgery, high risk surgical patients are not usually identified and strokes can be missed, leading to fewer treatment options and more complications. My previous pilot study showed that anesthesia and surgery can limit the accuracy of standard screening tools for stroke. We urgently needed a screening tool and protocol specifically for surgical patients. We also don’t understand well how patients recover after perioperative stroke, such as which patients survive, and whether they can stay in their homes. Building on our prior research, this multiphase study aims to: (1) Understanding which patients do poorly after perioperative stroke and whether those factors can be changed; (2) Compare mortality and other complications after stroke between those who had recent surgery and those who did not; and (3) Identify a useful perioperative stroke screening tool to quickly and accurately detect stroke after surgery.
Award Partner: Providence Research
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.
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.
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.
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.
- 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)