What does it take to outwit lung disease? Bold, brave research! Our investigators are involved in projects that cover all the bases, from studying how diseases work to developing real-world therapies.
Below, you’ll learn more about the research projects we are currently funding. Interested in applying for a research grant? Learn about our opportunities here.
Infectious Disease Research Projects
Dr. Jane Batt
Genomic Epidemiology of M. Abscessus in Pulmonary Disease
Amount Awarded: $44,450
Mycobacterium abscessus, a member of the non-tuberculous mycobacteria (NTM), is an emerging respiratory pathogen in people with chronic lung disease. In the Cystic Fibrosis (CF) patient, M. abscessus infection is associated with worsening lung function and poor outcomes following lung transplantation. Treatment of the organism requires months of therapy with multiple poorly-tolerated antibiotics. Since M. abscessus is multi-drug resistant, cure is often impossible. Given its increasing occurrence and its negative impact on the health of people with lung disease, prevention of infection is vital. Infection with NTM was thought to occur exclusively from the environment. This dogma has been recently challenged for M. abscessus. Using a novel technique called Whole Genome Sequencing (WGS), which reads the unique genetic code for each bacteria, researchers in the UK in 2016 presented evidence that was highly suggestive of M. abscessus person-to-person spread among CF patients. However, they did not provide epidemiologic support to confirm transmission, nor did they did determine whether this potential transmission was unique to CF, or also occurring in patients with other lung diseases.
Currently, there are no special infection control measures implemented in Canadian hospitals for the non-CF patient with M. abscessus. In contrast, CF clinics in Toronto recently undertook special infection control precautions and now only assess M. abscessus patients in negative pressure rooms. These rooms are an expensive, limited hospital resource that are essential to treat patients with dangerous respiratory infections that spread person-to-person and can infect an entire population, such as tuberculosis. Our lack of understanding of how M. abscessus is spread is limiting our ability to provide sound, safe, and cost-effective care.
We aim to determine whether there is evidence supporting possible person-to-person transmission of M. abscessus occurring in Ontario hospitals with current infection control practices in place. We will perform WGS of M. abscessus isolates from patients treated in 3 Toronto hospital specialized CF clinics and NTM clinics. Sharing of highly genetically similar organisms between patients will support the possibility of person- to- person spread; genetically distinct organisms in different individuals will not.
We will be the first group to assess for potential strain sharing of M. abscessus in Canadian CF centres, and the first worldwide to assess for potential strain sharing in patients with non-CF related lung disease. Our project provides immediate value to Canadians. It will inform current infection control (IC) measures, as we will provide precise, scientific evidence hospitals can use to adjust their IC practices in CF and non-CF lung disease patients. If we demonstrate strain sharing this project will provide critical pilot data for future study to determine how the organisms are spread (ie droplet vs aerosol) and how M. abscessus subspecies impact lung disease progression and treatment outcomes.
Dr. Sarah Wootton
In vivo Adeno-Associated Virus (AAV) Surfactant Protein B gene delivery system for lung regeneration
Amount Awarded: $49,998.50
The lung is made of pipes (conducting airways) that deliver oxygen to millions of air sacs (alveoli) where oxygen is taken up by the blood and distributed to the rest of the body. These air sacs are coated with surfactant. Surfactant keeps the air sacs wide open to insure exchange of oxygen. Surfactant is made out of a mixture of proteins and lipids and produced by lung cells (called type 2 alveolar epithelial cells, AEC2). Amongst these surfactant proteins, surfactant protein B (SP-B) decreases lung surface tension to keep the alveoli wide open. Unfortunately, there is a rare, but lethal genetic disease in which SP-B is abnormal. The gene that produces SP-B protein is called SFTPB. Babies born with mutations in SFTPB have trouble breathing at birth because the alveoli are crumpled and cannot open. These babies usually die. Currently, there is no therapy except lung transplantation, which is not always possible.
Our goal is to deliver the healthy SFTPB gene into the lung by using gene therapy in animal models of SP-B deficiency. We will take advantage of a unique recombinant adeno-associated virus (AAV) that we have engineered to be stable and highly efficient in targeting the lung. This is a safe, replication defective viral vector that can target AEC2s. We will deliver the healthy SFTPB gene into the lungs of a mouse model of SP-B deficiency. We will test if this genetic tool can improve the breathing problems of these mice. We are combining the expertise of two Ontario scientists that have decades of training in our respective fields. I have trained my entire career on viruses and how to engineer them for therapeutic purposes. Dr. Bernard Thébaud is a clinical neonatologist caring for critically ill babies and a research scientist that has made it his mission to develop cures for lung diseases in babies.
Delivering the SFTPB gene with our AAV vector into an animal model of SP-B deficiency has never been attempted. If successful, we will have provided proof of concept that this technology can lead to a cure for a lethal genetic lung disease. It could also benefit other genetic diseases for which there is no treatment today. The mission statement of the Lung Health Foundation is “to lead nationwide and international lung health initiatives, prevent lung disease, help people manage lung disease and promote lung health.” The proposed research tackles an important lung problem: to provide a treatment for patients with genetic lung diseases who either die at birth due to a genetic defect or contribute to 10% of pulmonary fibrosis patients. The proposed research will test a new approach to correct the genetic defect using a new gene therapy approach as a life-saving therapy. Our study will provide proof of concept for the feasibility and efficacy of such an approach. Our study has the potential to save the lives of babies world-wide. Importantly, the results of our study will be relevant to other life-threatening genetic lung diseases that currently lack treatments.
Dr. Ruud Veldhuizen
Post-natal effects of intra-uterine growth retardation on the lung and its response to sepsis
Amount Awarded: $50,000
Our lab studies a condition call Acute Respiratory Distress Syndrome which has no known cure and a mortality rate of 30-40%. Research studies have investigated this disease however, most of those studies utilize healthy adult male animals despite the fact that ARDS occurs in males and females at different ages and often in people susceptible to the disease. Our goal is to use animal models of the disease that better reflect the human population, specifically, we propose that low birthweight may be a risk factor to ARDS in the pediatric population.
The two objectives of our proposal are:
- To use an rat model of low birthweight to test the effects this may have on the lungs after birth.
- To test if rats with low birthweight are more susceptible to developing lung injury.
Both these objectives will investigate male and female animals.
We will use a rat model of low birthweight induced by feeding the pregnant rats a low protein diet. The lung injury will be induced by exposing young male and female rats to sepsis, which is an infection that commonly lead to ARDS. Our laboratory specializes in lung physiology and biochemistry, thus the offspring of these animals are examined using a variety of techniques related to lung function and injury.
The main novelty of our studies is the utilization of animal models that accurately reflect the human conditions; specifically, we investigate the effect of low birthweight on lung injury in the pediatric male and female population. As there is no “one-size-fits-all” pharmacological therapy for patients with ARDS, our experiments will help in the development of future studies that uses a more personalized approach to treatment, taking in consideration the sex of the patient, the age and the presence of potential risk factors. Ultimately, our studies may contribute to the improvement of the mortality and morbidity associated with sepsis-induced ARDS.
Our proposal focuses on ARDS which is a pulmonary condition with a high mortality rate. Our studies may ultimately contribute to the design of new therapeutic approaches for this disease based on a better understanding of the factors that influence the development and progression of this condition.
Dr. Bryan Heit
Bacterial Modulation of Alveolar Macrophage Efferocytosis During Pneumonia
Amount Awarded: $49,550
Pneumonia – infection of the lungs by pathogens such as bacteria – are a major cause of hospitalization and death among Canadians. Many pneumonia survivors experience a severe and lasting loss of lung function; the consequences of this range from long-term disability to death. In fact, the likelihood of a pneumonia patient dying from a post-pneumonia complication is higher than the likelihood of a patient dying from the complications of a heart attack or stroke. Clearly, better treatments for recovering lung function are required for pneumonia patients, both to restore normal lung function after disease, and to prevent the deaths resulting from post-pneumonia complications.
We and our collaborator have recently discovered that the ability of lung macrophages to remove dead and dying cells – a process termed ‘efferocytosis’ – is required for the recovery of lung function, with poor efferocytic capacity resulting in a poor recovery of lung function. We have also discovered that Staphylococcus aureus, a bacterial pathogen responsible for many cases of pneumonia, can use dying lung cells as “Trojan horses” to infect other cells, and in doing so, creates the efferocytic defects that lead to poor recovery of lung function. In this proposal, we will determine how lung macrophages process Staphylococcus aureus encountered as a “Trojan horse”, and how encountering “Trojan horse” pathogens lead to defects in efferocytosis.
We have developed a model system of Staphylococcus aureus “Trojan horse” infection which results in macrophages with efferocytic defects similar to those seen in human pneumonia patients. Using this model and live-cell microscopy, we will investigate how Staphylococcus aureus taken up as “Trojan horses” are processed by lung macrophages, specifically investigating whether the macrophage treats these “Trojan horses” as though they were a dying cell or a pathogen. Secondly, we will quantify which genes are active in macrophages after taking up these “Trojan horses” in order to understand how the macrophages are “programmed” to be poorly efferocytic. This will allow us to understand the processes that lead to a loss of efferocytic function and failed lung repair in pneumonia patients.
The discovery that the efferocytic capacity of lung macrophages determines the recovery of lung function following pneumonia was made less than a year ago by my collaborator. To our knowledge, the model system we have developed exists no where else in the world. As such, we are in the unique position to investigate both “Trojan horse” infection in pneumonia, and the resulting loss in efferocytic capacity of lung macrophages.
This proposal is directly focused on understanding how and why lung function is lost following pneumonia. This work may lead to treatments which restore efferocytosis in pneumonia patients, thereby preventing the loss of lung function that is an all too common result of pneumonia. This would directly improve the lung health of the approximately 11,000 Canadians who die of pneumonia and the resulting loss of lung function each year.
Dr. Jim Jian Sun
Restoring macrophage function against tuberculosis
Amount Awarded: $50,000
Tuberculosis (TB), a contagious respiratory disease of the lung caused by inhaling the bacterium Mycobacterium tuberculosis (Mtb) is responsible for over 2 million deaths each year. While antibiotics are usually effective in treating TB, the emergence of drug resistant Mtb strains coupled with the lack of new anti-Mtb drugs renders treatment increasingly difficult. Inhaled Mtb are engulfed by special cells in the lung called macrophages, which normally kill invading bacteria. However, Mtb reprograms host macrophages to deprive their ability to kill the bacteria, which leads to disease progression. We have identified a host cell protein (PPM1A) that Mtb hijacks to shut down the killing function of these immune cells.
Our objectives are now to understand how this protein controls the ability of our immune cells to kill invading bacteria, and to identify drugs that can target this protein to restore the normal function of macrophages. This approach to target host cells instead of the bacteria will have the potential to boost the ability of our immune cells to eliminate Mtb, which can be developed as a unique and alternative treatment strategy against TB. Importantly, because host-directed therapy is aimed at boosting the body’s own immune system, the results from this research will be applicable to a variety of other infectious bacterial diseases that affect lung health such as pneumonia.
The advancement of this strategy is critical as it is becoming increasingly clear that the goal of a complete eradication of Mtb is unlikely if we strictly depend on antibiotics targeting the bacterium. A host-directed therapy approach holds immense promise for the development of adjunctive TB therapy in the future because this strategy would circumvent major problems associated with the development of antibiotic resistance. As such, the proposed research aligns with the mission of the Lung Health Foundation to promote lung health by preventing, treating, and ultimately eliminating deadly lung diseases such as TB. The threat of TB in our country persists as multi- and extreme-drug resistant Mtb strains are now common and increasingly cause infections even in developed countries, which render many front-line drugs inadequate. Alarmingly, a recent statement by WHO strongly warns that efforts to beat tuberculosis fall far short. The proposed research will thus become an essential piece of the puzzle to advance host-directed therapy efforts against TB with the prospect of eliminating this deadly disease, a long-standing mission of the Lung Health Foundation.