TIME for Translational Medicine at Queen’s University: A road map from Molecules to Populations - 2nd installment

| 1 February 2018

In the 1^st edition of this blog, I introduced TIME, the Translational Institute of Medicine, an initiative being launched in the DOM in 2018. TIME includes a new Graduate program (MSc and PhD), new infrastructure and a new web resource, linking trainees and investigators to one another and to vital resources (human and infrastructure). We heard from Dr. Charles Hindmarch, Dr. Rachel Holden and Dr. Paula James. Their research programs help illustrate what we mean by translational medicine. In this 2^nd edition, we will hear from 3 more young Clinician-Scientists: Dr. Yuka Asai (Dermatology), Dr. Amer Johri (Cardiology), and Dr. Gord Boyd (Neurology). Their exciting research program further emphasizes the importance of a translational approach to research and Medicine.

Dr. Yuka Asai, Queen’s Department of Medicine, Division of Dermatology

The goal: To figure out why people get food allergies. In doing so, we may also shed light on other allergic diseases, which may have the same root causes. The problem: Allergic diseases are common. We don’t know why this is, although research suggests there are both inherited (genetic) and environmental factors driving the development of food allergies. Although I am a dermatologist, my research is focused on food allergy, specifically peanut allergy, which has a prevalence of approximately 1% in adults and 2% in children in Canada. Peanut is the most common cause of severe reactions to food, especially in children where it causes approximately 20-25% of cases of anaphylaxis. The big idea: Why do people get allergic to things? We know there is a genetic component: asthma, eczema, rhinitis (hayfever), and food allergies run in families. We know that environmental exposures influence whether someone gets an allergy. For example, factors such as eating peanuts at an early age, avoiding eating peanuts, or even how peanuts are prepared can influence the risk of peanut allergy. Decorative Image

Images courtesy of Dr. Gary White; RegionalDerm.com

Why is there an association between eczema (top) and peanut allergy? Key research observations: My work in allergy was initially triggered by the identification of the eczema gene and its role in skin barrier function. Knowing that eczema, a common itchy skin condition that results from a barrier defect in the skin, and peanut allergy often co-exist prompted me to search for a role for abnormalities of the eczema gene in people with peanut allergies. We found the link between the two, with the odds of having a mutation in the eczema gene between 2 and 5 times higher in those with peanut allergy than in people who don’t have peanut allergy. The relationship could be due to what is called the Lack hypothesis, or dual antigen hypothesis, which is the idea that exposure through the skin leads to allergy to peanut, and exposure through the gut leads to tolerance to peanut. However, we know that not everyone with eczema gets a peanut allergy. This led us to look for further genes that could be involved in the development of peanut allergy. Two thirds of people with peanut allergy in our research study also have asthma We then did a technique called a genome-wide association study, and have identified new shared risk loci (sites within genes that are linked with having a disease) for peanut/food allergy. These include histone-related proteins, such as EMSY, and HLA-DQB1. These genes are involved in gene-environment interactions (epigenetics): histones control how DNA can be open and closed, and methylation controls how genes can be turned on and off. HLA is a type of gene that can be turned on and off from environmental factors and which regulates allergy and inflammation . We also identified some new potential hits within or near genes that are related to food allergy, like CTNNA3. This is also interesting because these genes have also been seen in genetic studies of eczema and also for asthma. This leads to the suggestion that the same genes are responsible for allergic conditions of all types, and that environmental stimuli (diet, habitat, etc) are responsible for turning them on and off through epigenetic mechanisms. We have also confirmed our findings with collaborations with international food allergy research groups around the world. This discovery, was the topic of my PhD thesis. Like many translational discoveries this required a highly-motivated team and lots of funding. My collaborators include researchers in the Canadian Peanut Allergy Registry (Dr. Ann Clarke, University of Calgary; Dr. Moshe Ben-Shoshan, McGill University) as well as our national team of collaborators. The research was funded by the AllerGen NCE, CIHR, the Montreal Children’s Hospital Foundation, McGill University Health Centre Foundation, the Canadian Allergy, Asthma and Immunology Foundation, and the Canadian Dermatology Foundation. The support of key stakeholder groups was also crucial (Food Allergy Canada, the Allergy and Asthma Information Association, Allergies Québec, the Sandbox Project, Clean Air Champions). Understanding the discovery would not have been possible without our statistical team led by Denise Daley (University of British Columbia). The way forward: The identification of these factors could lead to a genetic risk index to identify people at risk for allergy for early intervention, and new therapeutic targets. For example, if we can identify which gene variants (for example, filaggrin, EMSY and HLA) are present, we could predict if you have a very high or very low risk of peanut allergy and plan accordingly, especially since interventions such as introduction to peanut via an oral route at an early age appears to prevent peanut allergy. Our group is pursuing these targets with further analytical work on the data, as well as looking at what these genes could be doing in food allergy, through new collaborations with Dr. Anne Ellis and Dr. Mark Ormiston at Queen’s. Final thoughts: Translational medicine is often portrayed as a linear flow – from the bench, to the bed, to the community. Our work has shown that this translation may need to be bidirectional and simultaneous. It also shows the size of the team required to make these discoveries.

Dr. Amer Johri, Queen’s Department of Medicine, Division of Cardiology

Editor POCUS Journal www.POCUSJournal.com

The big picture question: Can we predict heart attacks (blockage of heart arteries) by advanced imaging of the more accessible arteries supplying blood to the brain (the carotid arteries)? Can this (carotid plaque neovascularization), predict this (coronary disease and heart attack)?

Decorative Image

Defining The problem: It is thought that the majority of cardiovascular (CV) events are caused by soft, rupture-prone deposits of fat and cholesterol in the blood vessel wall. These fat-filled “volcanos” are termed “vulnerable plaques” (1, 2). If we find vulnerable plaques in one part of the vascular tree- for example the neck vessels this may predict vulnerable or dangerous lesions around the heart thus identifying the ‘vulnerable patient’.
The Big Idea: We know that vulnerable plaque lesions may be characterized by new vessel growth, similar to a tumor. Our big idea is to detect this new vessel growth (or neovascularization) using a special ultrasound technique known as contrast enhanced ultrasound. This type of contrast is made up of safe micro-bubbles of air that can enter these small vessels so that they ‘light up’ under ultrasound and can be detected.
Anticipated Key Research Observation(s): We plan to combine the expertise between CINQ (CINQLab.com), and the Rival Lab (www.rivallab.com) from Queen’s Department of Mechanical and Materials Engineering to track microbubbles from contrast enhanced ultrasound (shown by red arrows in Figure 3). These off-line computational techniques will allow us to measure flow inside the neovessels of a vulnerable plaque.
The Way Forward: As the rate of risk factors for heart disease continues to skyrocket, the burden of heart disease threatens to overwhelm our healthcare system. There is a crucial need to develop imaging expertise to detect the disease earlier, to quantify progression, and guide prevention and intervention. Our research adds a unique dimension in defining the diagnostic value of Contrast-enhance ultrasound (CEUS) of the carotid artery for CV risk stratification. In the future, we hope a simple, non-invasive test will help detect dangerous lesions and hence the vulnerable patient.

Dr. Gord Boyd, Queen’s Department of Medicine, Division of Neurology and Critical Care

Decorative Image

Big Picture Question: How can we preserve brain function in critically ill patients in the intensive care unit (ICU)?

Decorative Image

The Goal: Define the neurological consequences of critical illness.

The Problem: Nearly a quarter million Canadians are admitted to an Intensive Care Unit (ICU) every year. Tremendous improvements have occurred with regards to preventing death in the ICU. With decreased mortality however, comes increased recognition of the poor functional outcomes experienced by some ICU survivors. Many ICU survivors experience changes in brain function, including significant cognitive and functional deficits, which likely reduce their quality of life and independence. Developing strategies to prevent poor neurological outcomes after critical illness is difficult because we do not understand how the brain is damaged in ICU patients who have a severe illness that does not involve direct head injury.

The Big Idea: The overall aim of my research program is to develop therapeutic interventions to improve neurological outcomes in people with critical illness who require hospitalization in an ICU.

Decorative Image

The Key Research Observations: Using non-invasive techniques, including NIRS, near infrared spectroscopy, we can noninvasively measure brain blood flow. Our data suggest that poor brain oxygenation contributes to acute neurological dysfunction in critically ill patients. We are using similar technology to determine whether this also holds true for patients undergoing dialysis for renal failure, or cardiac surgery for blocked coronary arteries. In addition, we are using new techniques to identify novel biomarkers of brain injury. We hope that these techniques can be used in real-time to assess brain perfusion in ICU patients. We use robotic devices to quantify the degree of neurological impairment in our patients, allowing precise measurement of subtle brain function problems. The Way Forward: We are initiating a multi-centre study across Canada to validate our initial findings. Should we find a consistent link between poor brain oxygen delivery and neurological outcomes, the next phase will be to design precision interventions for our patients to improve their brain oxygenation, and thus their functional outcomes. The interested reader is referred to references at the end of this blog.

In the upcoming 3^rd and final edition of this blog on Translational Medicine, we will feature the research of Dr. Mark Ormiston and studies from my lab. Tune in to find out more about the importance of translational medicine in research in general and in TIME @queensudom in particular.

Relevant references: Dr. Johri References

Virmani R, Kolodgie FD, Burke AP, Finn A V, Gold HK, Tulenko TN, et al. Atherosclerotic Plaque Progression and Vulnerability to Rupture. Arterioscler Thromb Vasc Biol. 2005 Sep 30; 25(10):2054 LP-2061.
Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Vol. 113, Circulation. 2006. p. 2245–52.
Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From Vulnerable Plaque to Vulnerable Patient. Circulation. 2003 Oct 6; 108(14):1664 LP-1672.
Staub D, Schinkel AFL, Coll B, Coli S, van der Steen AFW, Reed JD, et al. Contrast-Enhanced Ultrasound Imaging of the Vasa Vasorum: From Early Atherosclerosis to the Identification of Unstable Plaques. JACC Cardiovasc Imaging. 2010; 3(7):761–71.
Feinstein SB. Contrast Ultrasound Imaging of the Carotid Artery Vasa Vasorum and atherosclerotic Plaque Neovascularization. J Am Coll Cardiol. 2006; 48(2):236–43.