Inflammation in Chronic Disease – Featured researchers

Team Grant: Health Challenges in Chronic Inflammation

John Brumell

Dr. John Brumell

NADPH oxidase function in the pathogenesis of pediatric IBD and JIA

Pediatric Inflammatory Bowel Disease (IBD) and Juvenile Idiopathic Arthritis (JIA) are two of the most common inflammatory diseases in children in Canada. Children living with these diseases continue to suffer from them throughout their lives. Both IBD and JIA have complex origins stemming from a combination of genetic and environmental factors. Genetic studies have found a connection between a person’s susceptibility to these diseases and the presence of mutated or compromised NADPH oxidases in their genes.

This team of researchers at Toronto’s Hospital for Sick Children hypothesize that these variants underlie common reasons for what causes IBD and JIA. The investigators will examine the genetic, immune, microbial and environmental factors connected to the variant NADPH oxidase which leads to IBD and JIA.

Objectives

The objectives of this proposal include:

  1. Identifying the genetic variants/mutations in the NADPH oxidase genes in IBD and JIA patients
  2. Determining how the compromised NADPH oxidase affects immune functions and
  3. Intestinal microbiota in JIA and IBD patients; and
  4. Identifying environmental factors (eg. breastfeeding, early life infections, antibiotics, vitamin D) that affect such patients and determine best ways to treat them.
NADPH Oxidase Function in the Pathogenesis of Pediatric IBD and JIA – Dr. John Brumell Interview
Transcript

Title: Dr. John Brumell, Co-Director, Inflammatory Bowel Disease Centre, The Hospital for Sick Children

I’m John Brumell. I’m a basic scientist at the Hospital for Sick Children in Toronto. I’m the lead of one of the CIHR Team Grants in the Inflammation Initiative. My research project will examine the role of NAPH Oxidase genes in the pathogenesis of inflammatory bowel disease and juvenile idiopathic arthritis.

These are serious inflammatory disorders that affect children and adults and the question is what genes are affected and what do those gene alterations do to the inflammatory response.

I’m a basic scientist. My research is into host pathogen interactions. Basically, how bacteria interact with our cells. Many of the genes we are studying in the context of these infections turned out to be linked to inflammatory disorders like inflammatory bowel disease and juvenile arthritis. And so we saw a great opportunity to be able to apply what we were learning about bacterial infections and apply it to the study of these inflammatory disorders in children.

We believe that by studying these pathways from our basic research, we can come up with new candidates to look for genes in patients with inflammatory disorders.

I would say in general that inflammation is really the key medical challenge of our time and that as we move forward, we have to put a lot of resources into studying this particular issue in medical science. And this initiative that has been started is, I think, a fantastic step forward in this direction.

Read an interview with Dr. Brumell discussing the project.

Johannes Eksteen

Dr. Johannes Eksteen

A multidisciplinary approach to target chronic inflammation of the gut, liver and joint

Chronic disease accounts for more than half of all healthcare spending in Canada. Amongst these, chronic inflammatory diseases affecting the gut (Inflammatory Bowel Disease, IBD), liver (Primary Sclerosing Cholangitis), and joints (Rheumatoid Arthritis) share many genetic and immunological features and often all occur in the same individual.

Traditionally these diseases have been studied separately but given how they are intricately linked at multiple levels it justifies a different approach to study them as a whole by integrating existing knowledge and exploring emerging therapies, not based on specific diseases but rather shared immune driven processes which are at the core of these diseases. By targeting chronic immune mediated end-organ damage we hope to alter the significant disability and premature death that is associated with gut, liver and joint disease.

Objectives

The objectives of this proposal are to use a trans-disciplinary approach with a research team based at the University of Calgary to investigate the molecular and clinical overlap between these different diseases to define shared disease pathogenesis using gene-informed and environment-altering biology. Once shared mechanisms are known, this knowledge can be used to improve patient care, accelerate discovery of better treatment methods, and develop cost-effective ways of disease management.

John Esdaile

Dr. John Esdaile

PRECISION: Preventing complications from inflammatory skin, joint and bowel conditions

Five million Canadians suffer from various chronic inflammatory diseases, including eight in particular which have been demonstrated to involve complications such as cardiovascular diseases, severe infections, bone, tissue, and metabolic complications. With markedly improved control of the acute effects of inflammatory disease, the major causes of morbidity and premature death now stem from these complications. This research team based at the University of British Columbia will study about 600,000 of the five million Canadians living with any of the eight diseases: psoriasis, rheumatoid arthritis, systemic autoimmune rheumatic disease, ankylosing spondylitis, gout, osteoarthritis, Crohn’s disease and ulcerative colitis.

Objectives

The objectives of this study are to:

  1. assess the risk and burden of the complications arising in chronic inflammatory disease
  2. assess the role of inflammation in causing complications and the impact of inflammation treatment on the frequency of the complications
  3. evaluate selected health services prevention interventions (for example, evaluating patient education and text messaging to improve adherence) or proof of concept studies (such as improving quality of care to prevent complications by placing reminders in electronic medical records; using case manager intervention for Aboriginal peoples)
  4. develop and assess a digital media physical activity monitoring and communication device to stimulate patient activity.
PRECISION: Preventing complications from inflammatory skin, joint and bowel conditions – Dr. John Esdaile Interview
Transcript

I’m John Esdaile. I’m a professor of medicine at the University of British Columbia. I’m an arthritis specialist and I’m the Scientific Director of Arthritis Research Canada.

We’re looking at a group of inflammatory diseases… the joint diseases include things like Rheumatoid Arthritis, Lupus, and all sorts of diseases related to Lupus…gout, even things like osteoarthritis. Other groups of inflammatory diseases include psoriatic arthritis and spondylitis. But we’re also looking at skin disease, psoriasis and inflammatory bowel disease.

We think all of these diseases share a number of complications that as we got better and better at controlling the acute problems of these diseases, we’d be left with chronic, low-grade, ongoing inflammation, which results in a cascade of complications which are now more important than the problems we used to fight before we had better therapies.

And these complications include things like heart attacks, strokes, lung clots, hip fractures, diabetes, lung disease and hospitalized infections, serious infections. So we believe that these inflammatory diseases, as we get better at controlling some of it, resulting in complications from low grade inflammation.

Our interest is one in linking the complications to the inflammation and then actually intervening to get rid of that low grade inflammation and therefore completely preventing these complications.

We have some evidence that we may be able to do that and we are rather excited about the prospect of radically altering these bad outcomes.

Read an interview with Dr. Esdaile discussing the project.

Paul Kubes

Dr. Paul Kubes

Intravascular immunity in chronic inflammatory lung diseases

Until recently, being able to look closely at lung vasculature (structures of blood vessels) has been limited. With modern imaging technology, fundamental information needed to treat chronic inflammatory lung disease is now possible to obtain. With new imaging data, researchers are beginning to understand the function of innate immune cells in lung vasculature. They have thus established a hypothesis that within the lung there are various different cells regulating immunity to inflammation, and significantly, all of these cells are based in the lung vasculature. During different conditions such as infection, tumor development, normal sterile injury and repair, and fibrosis, the levels of inflammatory and anti-inflammatory cells fluctuate depending on the condition, with iNKT cells regulating the two types of cell populations.

Objectives

Now that iNKT cells are known to be linked to the lung’s immunity to inflammation, researchers involved in this study taking place at the University of Calgary will examine chronic sterile inflammation and chronic fungal inflammation. The changes that may occur over months of exposure to a pathogen or sterile inflammation is completely unknown and may dramatically change the lung environment to the point that it becomes permissive of cancers or in other cases, it may eradicate cancers. The research team will also study both metastasizing tumor cells and lung cancer under normal and chronic inflammatory conditions.

Ruth Ann Marrie

Dr. Ruth Ann Marrie

Defining the burden and managing the effects of psychiatric comorbidity in chronic immunoinflammatory disease

Not enough attention is given to the impact of psychiatric comorbidities (mental health illnesses occurring at the same time) of chronic immune mediated-inflammatory diseases (IMID) which affect more than five per cent of Canadians. The lack of diagnosis and treatment of these psychiatric comorbidities complicate management and subsequent outcome of the diseases. The unknown impact of the psychiatric effects of IMIDs on patients is a critical knowledge gap for patients, clinicians, and decision-makers.

Objectives

With the goal of enhancing the management of and gaining general insights into chronic IMIDs, this University of Manitoba-based multidisciplinary research team will compare and contrast the burden and interaction of psychiatric comorbidities of three particular IMIDs: inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA).

Specifically, studies will fall under two themes:

  1. examining the magnitude and impact of psychiatric comorbidity in IMID and
  2. determining effective diagnosis and management of psychiatric comorbidity in IMID.

Aims in the first theme will:

  • compare work disability and health-related quality of life in IMID patients both with and without psychiatric comorbidities, and in people with psychiatric disorders alone;
  • estimate the incidence and prevalence of psychiatric comorbidity in people living with IMID compared to the general public;
  • compare use of the healthcare system among IMID patients with - versus without - psychiatric comorbidities, compared to the general public;
  • estimate mortality rates in persons with IMID and psychiatric comorbidity compared to rates in those without, and rates in the general public.

Aims in the second theme are to:

  • validate ways for health care providers managing IMID to identify depression and anxiety;
  • develop resources for health care providers, patients and families to manage psychiatric comorbidities in IMID.

Jean Marshall

Dr. Jean Marshall

Restitution enhancement in arthritis and chronic heart disease

Two chronic conditions, myocardial infarction (MI) (heart attack) leading to cardiac fibrosis (abnormal thickening of heart valves) known as post-MI inflammation; and rheumatoid arthritis (RA) which culminates in joint destruction, are major health problems both in Canada and internationally.

These conditions happen as a consequence of the human body’s immune system responding improperly by causing inflammation. Costly to the healthcare system and challenging to treat, these conditions lead to disability from irreversible joint damage and death from heart failure. In both conditions, immune effector cells infiltrate affected tissue, which affects production of inflammatory mediators and tissue remodeling. Both conditions also involve the clinical outcomes of either:

  1. the disease resolving spontaneously or with the first line of therapy or;
  2. continuing with relentless myocardial or articular damage.
Objectives

This trans-disciplinary research team based mainly at Dalhousie University will define the critical processes associated with successful disease resolution in both post-MI inflammation and early rheumatoid arthritis with the aim of improving therapy.

The Restitution Enhancement in Arthritis and Chronic Heart disease (REACH) team research program will work toward improving targeted therapy, better identification of clinically important subsets of patients and an improved understanding of the fundamental mechanisms of inflammation resolution. In the long term, this work will translate to a reduced economic and social burden from these conditions.

The REACH team proposes to complete four projects to achieve its objectives:

  • Project 1 determines the clinical characteristics and biological mechanisms associated with resolution of post-MI fibrosis. A database of over 17,000 patients and examination of clinical material will be used to identify clinical and laboratory features of patients who have a successful outcome post-MI.
  • Project 2 examines patient data and patient material from Halifax, Winnipeg, and Helsinki to determine clinical and biological characteristics associated with long-term remission after first line therapy for early RA.
  • Project 3 will investigate how inflammation resolution and tissue restitution can be enhanced through modifying the function of mast cell and NK T cells, protease activated receptors and natural inhibitors of toll-like receptor signaling, using rodent models of myocardial fibrosis as well as in vitro human model systems.
  • Project 4 will involve collaborating with the Centre for Drug Research and Development and AllerGen NCE to employ best practices for knowledge translation and drug development to maximize the clinical impact of the first three projects.
Inflammation in Chronic Disease Team Grants: Restitution enhancement in arthritis and chronic heart disease – Dr. Jean Marshall Interview
Transcript

Title: Dr. Jean S. Marshall, Professor and Head, Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University

My name’s Jean Marshall. I’m the head of the Department of Microbiology and Immunology at Dalhousie University and I’m a basic scientist. I do fundamental work in Immunology.

The project we’re working on is something called Restitution Enhancement in Arthritis and Chronic Heart Disease which is a bit of a mouthful so we shortened it to REACH. We call it the REACH Program.

And it’s looking at both chronic heart disease in subjects just post-heart-attack so post myocardial infarction and in early arthritis, early Rheumatoid Arthritis.

In the case of people with heart disease, some people go on to congestive heart failure and in the case of arthritis, some go on to progressive damaging disease. We’re trying to work out not so much what goes wrong in those that get worse, but look much more closely at what goes right in those that get better with a view to exploiting those pathways to developing new therapies.

Inflammation is a natural process. We need inflammation. We need inflammation to heal, we need inflammation to respond to infection, so inflammation isn’t always a bad thing.

We need to understand inflammation in a way so that it can be regulated appropriately, for the appropriate setting. And inappropriate inflammation underpins an enormous range of different diseases so allergy, asthma, even Alzheimer’s disease, heart disease, joint disease, they all have aspects of inflammation underpinning all the processes that cause those diseases, so it’s really very, very fundamental to our understanding of many of the important, particularly the important chronic diseases that we need to address as researchers.

Read an interview with Dr. Marshall discussing the project.

David Park

Dr. David Park

Insights into Parkinson's disease, Crohn's disease, and leprosy: a common role for LRRK2

This project’s University of Ottawa-based multidisciplinary team will investigate shared molecular pathways that cause immune dysregulation in three chronic diseases including Parkinson’s disease (PD), Crohn’s disease (CD) and Hansen’s disease (leprosy). These three diseases represent a significant burden on health care costs and human suffering. PD is the number two cause of neurodegenerative diseases in the developed world, while leprosy is the number one cause of neuropathy in the developing world. Recent evidence published by members of the team indicate that LRRK2 function may be a common link between these seemingly disparate disorders due to its regulation of the human body’s natural immune response.

Objective

The objective of the research team’s goal is to provide a synergistic and comprehensive explanation for LRRK2’s role in immune dysfunction and chronic disease pathology. The team has developed a unifying hypothesis out of its members’ already-published research for LRRK2 function in “complex diseases” where a genetically susceptible host (i.e., one carrying a distinct LRRK2 genotype) encounters an environmental trigger such as a microbial pathogen and subsequently experiences a dysregulated response and expression of PD, CD, or leprosy. The unifying tenet of this proposed model for all three human conditions states that both genetic risk and an environmental trigger and passage of time are required for the disease expression to occur.

Dana Philpott

Dr. Dana Philpott

Nod-like receptors: linking innate immunity and inflammation to chronic disease

Chronic inflammation is central to the pathogenesis, progression and ultimate organ failure in chronic diseases increasingly affecting Canada’s growing elderly population. Cardiovascular, inflammatory bowel, and chronic kidney disease in their different forms are three such common chronic conditions. Nod-like receptors (NLR) are a family of innate immune genes that regulate inflammation associated with many of these chronic conditions and represent central and unifying players in the pathogenesis of inflammation and chronic disease.

Objective

The central hypothesis of this project, a partnership between the University of Toronto and the University of Calgary, is that the NLR genes play a significant and common role in the pathogenesis of inflammation and severity of chronic disease involving the heart, kidney and the gastrointestinal tract. With the expertise of researchers from the four research pillars of NLR biology, inflammatory bowel disease, chronic kidney disease and cardiovascular disease, this interdisciplinary team will focus on understanding and translating the biology of the NLRs to uncover novel methods for early diagnosis, stratification and monitoring chronic disease as well as developing new strategies for treatment.

Using existing infrastructure and resources that includes molecular reagents, genetic mouse models, human biobanks/biological samples and clinical/population/administrative health databases, the team will work to achieve two major aims:

  1. Conduct basic biomedical research to identify biomarkers and establish the basis for knowledge translation to develop ways to treat humans living with chronic disease;
  2. Once the biomarkers are identified, to translate them to human disease by linking data collected from patient cohorts to clinical and population/administrative databases to develop new methods to diagnose, stratify and monitor patients with these common chronic diseases.

Mark Swain

Dr. Mark Swain

Brain dysfunction in chronic inflammatory disease: reciprocal effects of CNS and periphery crosstalk

Chronic inflammatory diseases, such as rheumatoid arthritis, hepatitis and inflammatory bowel disease share many common features. Among the most significant of these are changes in the brain that lead to behavioral symptoms of fatigue, depression, cognitive dysfunction and social withdrawal.

Such debilitating symptoms markedly diminish the quality of life of hundreds of thousands of Canadians living with these conditions. One might think it natural for a patient with inflammatory bowel disease, liver disease, or rheumatoid arthritis to be depressed, anxious and distracted. This project’s research team contends that these behavioral changes are not a response to disease. Rather, a fundamental alteration occurs in the way in which the brain functions in the face of a chronic inflammatory disease.

Despite the impact of these symptoms, the mechanisms of brain dysfunction in chronic inflammation are not well understood. Furthermore, there is an increasing appreciation that altered central nervous system function has considerable consequences for disease progression; this too has not been explored.

Objectives

The objectives of this project are to address these shortcomings by understanding how persistent inflammation may cause disturbances in the brain and how chronic immune-mediated inflammatory diseases reprogram the brain to alter neuronal function, precipitating co-morbid behavioral dysfunction, which influences the disease processes.

The University of Calgary-based trans-disciplinary research team examining these important problems consists of experts in the management of chronic inflammatory disease: neuroscientists, psychiatrists and imaging experts who are fluent in understanding brain-body communication and plasticity of brain function. This unique basic-clinical-translational research team is poised to facilitate the discovery of common central mechanisms underlying the neurological and psychological conditions associated with chronic inflammation. Translating its discoveries to improve patient outcomes is the team’s ultimate goal.

Transplantation Research Initiative: Canadian National Transplant Research Program

Lori West and Marie-Josée Hébert

Dr. Lori West
Dr. Marie-Josée Hébert

Organ and bone marrow transplants are well-established treatments for patients with incurable medical conditions. However, major gaps and obstacles prevent transplantation from being fully effective.

We need to develop new knowledge, policies and health care practices to overcome these barriers. Our transplant research team brings together researchers and stakeholders across Canada from many disciplines to work in an integrated and coordinated manner to increase and improve the promise of transplantation as a 'second chance' at health for Canadians.

Our research program tries to unify the following projects:

  • Improving organs for transplant through targeted organ protection and repair
  • Increasing organ and cell donation through improved donor identification
  • Examining biologic markers of early problems in transplant function and identifying targets for drug treatments
  • Implementing strategies to avoid rejection of transplants and side-effects of medication
  • Predicting and preventing viral complications of transplantation
  • Targeting age-related and health care system problems experienced by children and teenagers with transplants
Objectives

To support these innovative projects, our program will integrate the management of experimental protocols, data, clinical trials, biobanks and registries across all studies. A core team will examine ethical, economic, legal and social issues related to transplantation.

Our team's critical priorities include creating and sharing knowledge with a wide range of stakeholders and training new transplant researchers to sustain progress into the future.

Overall, we aim to achieve improvements to donation effectiveness, to transplant policies and processes and to individual transplant outcomes.

By increasing the effectiveness of donation and transplantation, the proposed research will substantially improve the health of Canadians who are candidates for and recipients of solid organ and bone marrow transplants.

Canadian Microbiome Initiative

Kenneth Croitoru

Dr. Kenneth Croitoru

Influences of Host Genome on the Human Gut Microbiome: Studies in a Healthy Cohort Carrying Crohn's Disease Risk Alleles

Inflammatory bowel disease (IBD) affects more than 200,000 Canadians. The cause of IBD is thought to involve interactions between genetically determined immune responses to environmental challenges such as gut bacteria. We have started a prospective study of healthy people genetically at risk of developing Crohn's disease.

Objectives

This study will allow us to determine the differences in genes, environment exposure and gut bacteria that determine the cause of Crohn's disease. In collecting these healthy first degree relatives we will now be able to define the effect of genes on gut bacteria healthy people that carry the Crohn's disease risk genes.

We think that the composition of the gut bacteria is influenced by genes. To understand this we propose to:

  • characterize changes in the gut bacteria i.e. the Microbiome in healthy subjects carrying genetic mutations known to increase the risk of CD
  • define the gene content (metagenomic analysis) of these bacteria influenced by CD genes
  • identify and isolate specific organisms related to the metagenomic signals

The proposal will focus on a very unique collection of healthy subjects carrying genes involve d in the risk of developing Crohn's disease. The relationships between the host genes and gut bacteria are key to the maintenance of health and alterations may well be at the root of the cause of disease. The findings will be critical to developing strategies for prevention or treatment of IBD.

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