2018 Recipients of the Lupus Canada Catalyst Grant
Competition Catalyst Grant 2018-19
Application Metrics: 2/8 Applications Funded
Principal Investigator: Dr. Joan Wither
Institution: University Health Network
Project Title: Using CyTOF to dissect the interplay between Type I interferon and autoantibody production in Systemic Lupus Erythematosus
Funding Received: $35,000 Awarded
Project Lay Summary: In SLE antibodies are mistakenly produced against molecules that are part of the body, such as DNA and other proteins found in the nuclei of cells. These anti-nuclear antibodies (ANAs) deposit in the organs where the cause inflammation resulting in damage. SLE follows an unpredictable course, with the majority of patients undergoing remission and exacerbation. Currently, the immune mechanisms that distinguish periods of disease activity from inactivity are unknown, however the correlation between disease activity and levels of ANA as well as antibody secreting cells suggests that flares result from increased antibody production. Recently a novel B cell population, called ABCs, was identified that represent activated B cells that are poised to become antibody secreting cells. Using a mouse model of lupus we showed that administration of interferon, at levels similar to those seen in human lupus, was sufficient to promote development of ABCs. This led us to wonder whether one of the reasons that SLE patients with high levels of interferon have more severe disease is that interferon changes the function of their B cells making them more prone to become ABCs and consequently more likely to develop into antibody secreting cells. To address this question we plan to use a state-of-the art experimental technique, CyTOF, to examine the B cells in active and inactive SLE patients to determine whether they have been exposed to interferon and whether it has altered their function. If so, our experiments would support the use of interferon targeted therapies for flare prevention.
Competition Catalyst Grant 2018-19
Application Metrics: 2/8 Applications Funded
Principal Investigator: Dr. Murray B. Urowitz
Institution: University Health Network
Project Title: Identifying Antimalarial-Induced Heart Damage in Systemic Lupus Erythematosus
Funding Received: $35,000 Awarded
Project Lay Summary: Most patients with systemic lupus erythematosus (SLE) use antimalarials (AM) for many years, if not for life. Eye toxicity is a well-known side effect and patients are required to have an ophthalmology examination every 6-12 months. Heart damage has also been reported as a consequence of prolonged AM treatment, although sporadically. In such cases, AM are deposited in the heart and may cause heart failure and syncope. Diagnosis is usually delayed and almost half of the patients who developed this complication died. We aim to evaluate specific heart biomarkers (blood tests, namely troponin and brain natriuretic peptide, BNP) in the early identification of AM-induced heart damage.
Our preliminary studies led to early diagnosis in a small series of patients. Two hundred fifty patients will be screened for troponin and BNP. We expect that 20 patients will have abnormal biomarkers. Twenty patients with normal biomarkers (of the same age and sex) will comprise the control group. All patients will undergo cardiological investigations to exclude other causes of heart damage and identify how AM affect the structure and function of the heart.
Three distinguished academic centers will collaborate for this project with a team consisting of rheumatologists, cardiologists and radiologists. It is anticipated that the project will be completed in two years and render these biomarkers valuable in identifying subclinical heart damage. The impact on lupus patients who are taking AM for prolonged periods will be significant since early detection of heart damage will lead to improved survival.
Competition Catalyst Grant 2017-18
Application Metrics: 3/6 Applications Funded
Principal Investigator: Dr. Ann Clarke
Institution: University of Calgary
Funding Received: $34,500 Awarded
Project Title: Enhancing the Working Life of Individuals with SLE while Promoting Public Understanding: an Integrated Knowledge Translation Approach.
Project Lay Summary: Individuals affected by SLE experience considerable economic challenges. Their escalating and unpredictable health care costs and perpetual struggle to maintain regular employment and care for their families impact self-esteem, career trajectories, and role definitions. These are major and neglected concerns. In our ongoing research, we have used a mixed-methods (quantitative/qualitative) approach to better understand these issues. We surveyed over 1300 patients on their healthcare utilization and lost productivity. We conducted in-depth interviews with patients/patient advocates/physicians to understand how these economic issues affected patients and their families. SLE patients often pursue a less satisfying and financially stable career due to poor public understanding of the disease, limited workplace accommodation, and flawed government/workplace policies. To effect change, we need to look beyond individual or workplace interventions and focus on the systems-level (i.e., institutions, government, policies, and society). We are currently conducting workshops with stakeholders across Canada to identify the priority areas for targeting systems-level action. In our proposed research, we will develop and implement a novel integrated knowledge translation (iKT) initiative that supports the co-production of knowledge between researchers and knowledge users. It will address, for the first time in Canada, systems-level change to enhance the working life of individuals with
SLE and promote public understanding of the disease. We will work with a multi-stakeholder group to leverage the findings from our previous study and, through stakeholder consultations, webinars, and hackathons, develop systems-level interventions. This research will result in stronger stakeholder partnerships, ideas for specific and actionable systems-level interventions to enhance working life, and increased public awareness of SLE.
Competition Catalyst Grant 2017-18
Application Metrics: 3/6 Applications Funded
Principal Investigator: Dr. Joyce Rauch
Institution: Research Institute of the McGill University Health Centre
Project Title: RIPK3: A novel therapeutic target in SLE
Funding Received: $35,000 Awarded
Project Lay Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease that affects approximately one in every 1000 Canadians, and can result in life-long suffering and premature death. Individuals with SLE develop an immune response against their own cells and tissues, resulting in autoantibodies and organ damage. Current treatments of SLE focus on suppressing the immune system in general or the B cells specifically responsible for autoantibody production. Targeted therapies affecting key pathways implicated in the development of SLE, such as cell death and inflammation, are lacking.
We have found that a single gene encoding a protein called “RIPK3” is required for the development of autoantibodies and disease in a murine model of SLE. RIPK3 is a master regulator of cell death and inflammation. We will inhibit RIPK3 therapeutically to see whether we can prevent or improve SLE disease in two models of SLE: (1) mice in which SLE is induced experimentally (environmental trigger); and (2) mice that develop SLE spontaneously (genetic trigger). Our findings will provide proof of concept that targeting
RIPK3-dependent mechanisms in murine SLE results in prevention or improvement of this chronic and debilitating disease. These data could lead to Phase I trials of new therapeutic agents targeting RIPK3-dependent mechanisms in patients with SLE.
Targeting RIPK3-dependent mechanisms in SLE is a novel innovation that can impact both knowledge and patient care, and lead to improved treatments in SLE
Competition Catalyst Grant 2017-18
Application Metrics: 3/6 Applications Funded
Principal Investigator: Dr. Zahi Touma
Institution: Toronto Western Hospital – University Health Network; University of Toronto
Project Title: RIPK3: Improving the assessment and care management of everyday living limitations in adults with lupus related cognitive impairments: a multi-methods examination of activities of daily living.
Funding Received: $18,000 Awarded
Project Lay Summary: Over 35,000 Canadians live with widespread lupus related changes to body system functions and everyday activity involvement. One body system function area that can be affected is thinking skills. Cognitive impairments (CI, or issues in thinking skills) can include declines in memory, attention, planning, and thinking speed. It is estimated that up to two-thirds of people living with lupus experience CI. These changes can have a significant effect on daily activity involvement, which can then influence satisfaction with life. Currently there is no study examining the everyday activity function of people living with lupus related CI. Our research question is, do people living with lupus who do and do not have associated CI have different changes to their daily life? To address this question we will complete three studies. The first study will review all available studies examining daily life activities in people with lupus to identify possible lupus related changes. The second study will interview people with lupus related CI regarding how changes in thinking skills has affected daily life involvement. The third study will use a survey (developed from the results of study 1 and 2) to compare the self-reported daily activity changes of people with lupus and CI versus people with lupus and no CI.
The results of this project will improve future lupus care by providing foundational information to build more relevant and client-centered assessment instruments and treatment plans. This will help people stay involved in meaningful life activities and optimize satisfaction with life.
Competition Catalyst Grant 2016
Application Metrics: 2/6 Applications Funded
Principal Investigator: Dr. Murray B. Urowitz
Institution: University Health Network, Krembil Research Institute
Project Title: Scrutinizing the Heterogeneity of Systemic Lupus Erythematosus: Defining Phenotypes
Funding Received: $35,000 Awarded
Project Lay Summary: Lupus is a disease that mimics multiple diseases. The focus of this project is to phenotype patients, meaning to determine how clinically different lupus patients are from one another and how or why these differences exist. Lupus is characterised by unpredictable relapses and remissions in the majority of patients. However, in small proportion, lupus patients with monophasic pattern, meaning that these patients have active disease before and immediately after diagnosis and after some time they achieve prolonged remission. Interestingly, about half of these patients do so and require no medications. On the other end of the clinical spectrum, approximately 50% of the patients demonstrate persistent disease activity and usually have the highest risk for developing co-morbidities and irreversible damage. The objective of this study is to define distinct phenotypes of lupus based on disease course.
Competition Catalyst Grant 2016
Application Metrics: 2/6 Applications Funded
Principal Investigator: Dr. William T. Gibson
Institution: University of British Columbia
Project Title: Role of Topoisomerase Genes in Childhood-Onset SLE
Funding Received: $31,000 Awarded
Project Lay Summary: We are looking for rare mutations that are strong genetic risk factors for lupus in children. In a South Asian family with closely-related parents, we have found a rare mutation in a DNA repair protein called TOP1MT. We have also found two more rare genetic variants in TOP1MT in a group of nearly 50 children with lupus that started in childhood. Thus, we believe we have found a new “lupus gene,” and are seeking funds to prove what we think to be true – that rare mutations in TOP1MT cause childhood-onset lupus and may cause adult-onset lupus as well. If we are right, we will have a new angle on how to diagnose and treat some cases of lupus.