Research Pillar: Biomedical

IL-37 signaling via SIGIRR: A novel mechanism to suppress intestinal epithelial cell driven inflammation and dysbiosis

Patients with Inflammatory Bowel Disease (IBD) suffer bouts of extreme gut inflammation that disrupt the population of bacteria in their intestines. Consequently, IBD patients often have fewer beneficial bacteria and suffer an overgrowth of potentially dangerous bacteria. In healthy individuals, such responses are typically prevented by SIGIRR, a protein made by the cells that line the gut. 

SIGIRR acts by suppressing mechanisms that drive inflammation. Loss of SIGIRR dramatically increases inflammation and drives bacterial imbalance. The inflammation can become so severe that gut tissue can become necrotic. Currently, there is no way to promote the beneficial actions of SIGIRR in the gut. Recently, however, a newly recognized anti-inflammatory compound called interleukin (IL)-37 has been shown to interact with SIGIRR to inhibit inflammatory responses in human cells. 

Dr. Allaire will test whether IL-37 stimulates SIGIRR to: control inflammation and suppress bacterial killing responses in the cells that line the gut; protect mice from experimentally-induced IBD; and promote normal gut microbe balance. Results from this study will include an evaluation of the potential for IL-37 to act as a new therapeutic for patients with IBD.

 

Tissue engineered human cerebral blood vessels: A platform for lipoprotein studies on cerebrovasculature health

With every heartbeat, one quarter of all the blood in the body flows through the brain. This activity is essential for the health of neurons in the brain throughout life. Although scientists realize that understanding how to keep blood vessels in the brain healthy may offer new ways to treat brain disorders including Alzheimer’s Disease, a big challenge facing this area of inquiry is the lack of methods available to study the brain’s blood vessels outside of an animal model, which do not always mimic the human condition closely enough to provide answers that help to develop effective treatments for brain disorders. 

Dr. Robert has to date made considerable progress in being able to grow functional, three-dimensional and human-derived cerebral blood vessels in vitro using tissue engineering technology, and has used these vessels to analyze the accumulation of beta-amyloid peptide, which is a pathological hallmark of Alzheimer’s disease.
The primary goal of Dr. Robert’s research, in collaboration with the Canadian Consortium of Neurodegeneration and Aging , is to use this novel platform to better understand how blood and brain lipoproteins affect human cerebral vessel health. 

Although lipoproteins are traditionally known for their roles in carrying fats through aqueous body fluids, recent research has revealed that lipoproteins also influence inflammatory pathways and cellular signalling. Importantly, the composition of human lipoproteins are very different than their murine counterparts, and so far existing neurodegenerative disease mouse models have not been able to accurately model these differences. 

Dr. Robert’s innovative platform allows for mechanistic studies in a fully human experimental system. As such, the major translational plan for this research will be to disseminate findings to the academic and clinical communities through publication and presentations. As Dr. Robert’s methods use many technologies already established in cardiovascular medicine, the results will also be of significant interest to the medical and research communities and drive accelerated progress toward understanding the contribution of cerebrovascular dysfunction to dementia. 

 

Design and discovery of novel organ specific iron chelating system for the treatment of transfusional iron overload

Iron is essential for different physiological functions and biochemical activities in the body, but is extremely toxic in excess. Because humans don’t have an active mechanism to excrete excess iron, too much iron in the system can lead to iron overload. 

The mainstay treatment for many chronic anemia disorders is frequent red blood cell transfusions. Patients with such transfusion-dependent blood disorders are at a heightened risk of iron overload, which can cause severe damage to vital organs including the liver, heart, pancreas, thyroid and endocrine glands. Systemically accumulated iron is fatal if left untreated, and causes considerable morbidity and mortality. 

Iron chelation therapy is the most widely-used therapeutic approach to improve survival and reduce the risk of iron overload, by chelating and excreting excess iron using small molecular Fe (III) specific chelators. However, the current FDA-approved iron chelators have many limitations, including inefficiency, toxicity, severe side effects, high cost, and patient non-compliance. Consequently, the lifespan of a major portion of transfusion-dependent anemic patients is severely narrowed. To date, no methods are available for the excretion of organ-deposited iron. 

Recent developments in polymer/macromolecular therapeutic approaches shed new light on improving the therapeutic window of small molecular drugs and circumvent the limitations associated with existing therapies. Polymer therapeutics is a widespread multidisciplinary research area with a focus on polymer-conjugates of drugs and proteins, nano drug delivery systems and other macromolecular delivery systems. Several of such systems are approved for market arrival. 

Dr. Abbina’s research will investigate improving the success and efficiency of iron chelation by incorporating biodegradable moieties in a polyglycerol scaffold, and targeting specific organs that are susceptible to iron mediated toxicity. The result of this research will be liver- and heart-specific macromolecular iron chelation systems. 

The preliminary data is promising and we believe this safe and efficient therapeutic approach would benefit numerous patients suffering from iron overload induced diseases including cardiac failure or arrhythmia, cardiomyopathy, liver diseases and other endocrine disorders. This novel chelating system will also open new avenues to address other iron overload pathogeneses, including cancers, diabetes, inflammation and neurodegenerative diseases.

Protecting insulin-producing beta cell transplants from death and dysfunction

Diabetes is one of the most common chronic diseases among adults, children and youth. In 2008/09, the Canadian Chronic Disease Surveillance System reported 2,359,252 cases of diagnosed diabetes in Canada and a prevalence of 5.4% in British Columbia. Rates of type 1 diabetes (T1D) among children and youth have been on the rise globally. Poor control of diabetes leads to various complications such as cardiovascular disease, stroke, blindness and renal failure, resulting in a shorter and a reduced quality of life.

One of the major pathologies in diabetes is a deficiency of insulin, which is secreted from pancreatic beta cells. Patients with T1D require insulin therapy throughout their life because most of their beta cells are destroyed by autoimmune attack. Even through insulin treatment, reduced glycemic control makes complications and hypoglycemia-induced coma more likely.

Islet transplantation is a promising therapy for T1D that removes the need for insulin therapy. However, some limitations remain such as the supply of donor islets, the need for lifelong systemic immune suppression, and graft failure. Today, human embryonic stem cell (hESC)-derived surrogate beta cells are in clinical trials; however, it is likely that these cells will not be protected from immune attack.

Dr. Sasaki will generate CRISPR-Cas9-edited hESCs that can be differentiated to beta cells that express CCL22 in order to protect hESC-derived islet cell graft from immune attack. If this approach is successful, the results of this study will further the optimization of functional and immune-tolerant surrogate beta cells, which will help pave the way towards a cure for T1D.

 

Genetic etiology of progressive multiple sclerosis

Multiple sclerosis (MS) is the most common cause of neurological disability in young adults, other than trauma, with over two million people affected worldwide. Approximately 100,000 Canadians have MS, a rate that is nine times higher than the global average. MS symptoms vary widely and may affect vision, hearing, cognition, balance, and movement; negatively affecting many aspects of quality of life. To date, there is no cure or prevention for MS. Although treatments to effectively manage the clinical symptoms of MS are available, they come with several serious and even life-threatening adverse effects; and over time, MS enters a progressive phase which no known therapies can prevent or treat. MS was originally considered an autoimmune disease triggered by exposure to environmental factors, but family studies (twins, adoptees, half siblings) have clearly demonstrated an important genetic component to the disease.

The goal of this research program is to define the genetic components contributing to the onset of MS to provide new tools for scientific investigation and the development of novel and more effective treatments. To this end, Dr. Vilarino-Guell will apply new gene sequencing technologies to over 100 families with several blood relatives presenting with MS, as well as thousands of unrelated individuals diagnosed with MS. Within the last year he has identified disease-causing genetic changes for some of these families, as well as biologically-relevant genetic changes which impact disease progression and the severity of clinical symptoms. These genes and mutations have highlighted specific biological pathways implicated in the onset of progressive MS.

This research will further characterize the genes involved in these cellular processes to better understand the biological mechanisms of progressive disease. The results of Dr. Vilarino-Guell's research will provide the knowledge and tools for the therapeutic advances in the prevention and treatment of MS, tackling its highly debilitating progressive phase which is currently untreatable.

The role of the norepinephrine system in emotionally-biased attention and learning

Individuals vary widely in the aspects of the world they perceive and remember: some filter their environments through rose coloured glasses to perceive sources of pleasure, while others are attuned to signs of threat. Such affective biases in attention influence memory and characterize mood disorders and pathological responses to trauma as well as addictive behaviours. Yet much remains to be learned about neural mechanisms underlying such biases, and the factors that influence their development and potential for change.

Dr. Todd's research will investigate the influence of genetic variation and life experience on emotional biases in learning, attention and memory, and how they can be harnessed to treat affective disorders and addiction. This research will have a direct impact on our understanding of basic neural mechanisms underlying such affective biases, and increase our understanding of how genetic variation and life experience shape these mechanisms to produce behaviours linked to mood disorders and addiction, with important implications for assessing vulnerability and optimizing treatment.

Dr. Todd's five-year research program will work towards an understanding of the role of common genetic variations that influence neurochemical activity in the brain, and the development of behaviour patterns that are linked to mood disorders. Extending her previous work on the influence of genetics and trauma on emotional biases in attention, she will focus on understanding neural mechanisms underlying such biases; investigate whether such biases arise out of individual differences in patterns of emotional learning; and examine the influence of a common genetic variation that influences the availability of norepinephrine in emotional learning. The results of this research will aid understanding of the currently understudied role of norepinephrine in emotional learning patterns linked to mood disorders and addiction.

Gene clusters and natural products from the human microbiota

Worldwide, prematurity is the leading cause of death for all infants, with almost one million deaths per year. Babies born before 32 weeks face the worst odds. These babies are only 2% of births, but they account for over 1/3 of all infant deaths. For these infants, a disease called necrotizing enterocolitis (NEC) can be one of the most deadly complications of prematurity after the first week of life. NEC is an acquired condition in which intestinal tissue suddenly becomes inflamed and then begins to die off. NEC has a high mortality rate, and, even if the baby survives NEC, they are subject to considerable life-long health problems, resulting in tremendous costs to the health care system. With rising rates of prematurity, NEC poses a significant health and financial burden on Canada.

Dr. Ryan's research will employ approaches from biochemistry, microbiology, and chemistry to identify the factors produced by beneficial bacteria found in the infant microbiome that protect against NEC. This work will provide essential information for the development of novel therapeutics and preventatives for this costly disease.

Dr. Ryan will also collaborate with the Centre for Drug Research and Development to investigate molecules identified potential new drug leads, and researchers at the Child & Family Research Institute at the BC Children's Hospital to further investigate the role of the microbiome in infant health.

Identifying the molecular mechanisms underlying sex differences in fat storage using Drosophila as a model

In Canada, metabolic diseases (e.g. cardiovascular disease, type 2 diabetes, obesity) are leading causes of death, disability, and hospitalization. Currently, more than 10 million Canadians suffer from metabolic disease, with direct and indirect costs to the economy estimated to be $20 billion each year. Approximately 40% more men than women suffer from metabolic disease. In addition, commonly prescribed drugs used to prevent and treat metabolic disease are more effective in one sex than the other (e.g. fenofibrates). Despite these known differences in metabolic disease between men and women, prevention and treatment guidelines remain largely the same for both.

The main reason doctors do not treat men and women differently is due to lack of vital information about the fundamental metabolic differences between the sexes. The next step forward in preventing and treating metabolic disease is identification of the genes and pathways that control metabolism in each sex. This will provide researchers with a pool of promising new targets that will assist in developing therapies that will be effective in men and women, and eventually help in designing sex-specific treatment guidelines.

Dr. Rideout's research will work towards discovery of these genes and pathways using fruit flies as an innovative model, integrating the unparalleled genetic toolkit available to fly researchers with cutting-edge high-throughput metabolic analysis to answer three fundamental questions: firstly, which genes and pathways are essential for metabolic control in each sex; second, how sex-specific metabolic programs are established and maintained; and lastly, how sex differences in metabolism change in distinct contexts. Dr. Rideout will focus on sex differences in the regulation of fat storage, a key aspect of metabolism. 

Dr. Rideout's research outputs will be the identification of a pool of candidate genes that affect fat storage in each sex. Building on this vital starting point by translating this knowledge into pre-clinical models, and eventually humans, she will collaborate with world-leading experts in diabetes, obesity and cardiovascular disease in the Diabetes Research Group at The University of British Columbia. The innovative approach of this research program will make important strides towards developing personalized therapies for men and women, an important goal in modern medicine.

Studying genetic mechanisms of treatment resistance in non-Hodgkin lymphomas

Dr. Morin's research program will develop and apply laboratory and computational genomic methodologies that use DNA sequencing and other sensitive platforms to study the drivers of tumour onset, progression and treatment resistance in solid cancers in order to understand the somatic drivers of non-Hodgkin lymphomas (NHLs). Using massively parallel (next-generation) DNA and RNA sequencing, Dr. Morin will be able to identify somatic alterations and gene expression signatures in tumour tissue and liquid biopsies (circulating tumour DNA). To properly study such large data sets, he will utilize cutting-edge bioinformatics techniques and develop novel analytical approaches and pipelines that will allow leverage of unique sample processing techniques and applications.

Moving forward, this research will investigate aggressive subtypes of NHL including patients who typically fail standard-of-care treatments. Dr. Morin will rely on features of this malignancy such as high somatic point mutation rate, a well established list of known lymphoma-related genes, and the presence of clonal immunoglobulin rearrangements to develop assays to study the genetics of specimens from NHL patients in various ways. These include deep sequencing using a novel molecular barcoding system and digital PCR-based methods. He will continue to push the limits of sequencing technology by applying deep sequencing and whole exome sequencing to circulating tumour DNA. Under this research program, he will also continue to use a variety of laboratory and computational approaches to understand the clonal structure of NHLs, especially in the context of serial samples collected over the course of disease progression and after treatment failure or relapse. 

Dr. Morin's lab, along with the BC Cancer Agency, plan to pursue options to commercialize these strategies so that a broader group of users can use these techniques for research and clinical applications. Some of the research under this program will involve evaluating the performance of novel ctDNA-based methods to study tumour genetics and evaluate treatment responsiveness. This will be conducted in the context of prospective and retrospective samples from multi-centre clinical trials in Canada. This engagement with clinicians and publications describing these trials will help accelerate the adoption of such emerging technologies to the clinic.

Genetic dissection of neuronal pattern formation

Neurological diseases and disorders have been estimated to affect 3.6 million Canadians living in the community and over 170,000 Canadians living in long-term care facilities, including in British Columbia. However, we have limited information about the molecular mechanisms that cause many of those neurological conditions, largely because of the complexity of our nervous system. Therefore, understanding the mechanical processes that impart precise neural circuit formation using a simple model organism is critical to try to find ways to prevent neurological diseases and cure patients.

 

Toward this goal, Dr. Mizumoto will use nematode Caenorhabditis elegans as a model system to investigate the mechanisms that underlie neuronal circuit development. C. elegans has a short life cycle (3 days/generation) with a simple nervous system consisting of only 302 neurons, making it a great genetic model system to study the fine neural circuit formation. Most importantly, countless studies have shown that mechanisms and molecular machineries underlying the development of the nervous system are remarkably conserved between C. elegans and humans. It is likely that the knowledge obtained from our research will be directly applicable to the human nervous system and to diseases associated with nervous system defects.

 

Using C. elegans, Dr. Mizumoto will explore how neurons communicate with their neighboring neurons/cells to form a stereotyped neuronal pattern at the level of single synapse, which is a specialized interface between neurons or between neurons and other type of cells (such as muscle cells), to transmit electrical signals. Using a combination of C. elegans genetics, molecular biology and microscopy, this research will move towards an understanding of the fundamental principles of neural network formation.These studies will advance health-related knowledge by providing direct targets for other researchers to test in fruit fly (Drosophila) and mammalian models of neurodevelopmental disorders affected by Sema/Plexin signaling and others, and ultimately the development of therapeutic strategies for the treatment of these disorders.

End of Award Update: April 2023

Most exciting outputs

Many of the genes that we discovered from our research in specifying synapse formation are heavily associated with various neurological conditions, which suggest that our work may have potential to better understand the disease conditions affected by mutations in these genes.

 

Impact so far

As our work is fundamental and basic, we do not expect the impact of our work to be immediate.

 

Potential influence

We hope that our discoveries would lead to the development of therapeutics to treat neurological conditions in 20 years.

 

Next steps

We will continue to uncover the fundamental mechanisms of synapse pattern formation and specificity using C. elegans as a model organism.