CIHR Fall 2025 funding results for LMP faculty

Michelle Bendeck, University of Toronto

Calcification of arteries occurs in more than 1/2 of the population over the age of 60 and causes significant morbidity and mortality in diseases like atherosclerosis, diabetes, hypertension and in chronic kidney disease. 

Smooth muscle cells within the arteries deposit minerals in the extracellular matrix, in a process similar to the mineralization and hardening of bones, and this causes thickening, stiffening and sometimes rupture of these vessels. At present, there are no effective medical treatments to prevent or reverse calcification. Furthermore, calcified vessels cannot be angioplastied or stented, the two most common and successful treatments for atherosclerosis and peripheral vascular disease. 

We have recently discovered that a receptor protein which is expressed on arterial smooth muscle cells is responsible for calcification. This receptor, DDR1, causes a switch in the smooth muscle cells so that they start to behave like bone cells, and deposit minerals (calcifications) in the tissue. 

We seek to better understand the role of DDR1 in these processes during atherosclerosis, and the consequences for normal function of blood vessels. Importantly, we will test a new inhibitor for DDR1 in a mouse model of atherosclerosis, to see if we can inhibit calcification. 

Most of our work to date has been performed in tissue culture and mouse models. We will now for the first time investigate the expression and function of DDR1 in human diseased arteries. Our hope is that the work will lead to the development of new therapies designed to inactivate DDR1 and therefore prevent the calcification of arteries.

Phedias Diamandis, University Health Network (UHN)

Glioblastoma (GBM) is the most common and aggressive adult brain cancer. Despite intense research, outcomes are poor because GBM contains cancer cells with diverse properties, including some which are resistant to therapy. Moreover, a small number of patients survive much longer than expected, but these individuals are difficult to predict. 

We believe that current methods for studying tumors often miss the specific areas that drive these resistance and survival differences. To address these gaps, we are using artificial intelligence (AI) to analyze GBM tissue images. Our aim is to identify and study the specific areas within a tumor linked to either poor or exceptional patient survival. By combining AI with advanced molecular analysis, we can map the key biology that makes this cancer so aggressive and treatment-resistant. 

Firstly, we utilize AI to identify patterns in tumor images that correlate with good or bad patient outcomes. We use this to find "high-risk" areas and study them at a molecular level to understand what makes them so aggressive. 

Secondly, we use AI to find stable tumor regions that may remain after treatment and drive recurrence. We have discovered that some of these cells seem to be in a dormant state, which may make them resistant to therapy. This finding gives us new targets for potential drugs. 

Lastly, we propose to use a new high-resolution technology to study the edges of the tumor, where cancer cells spread into healthy brain tissue. Our data show that the types of cells in this area are unique and may be more difficult to treat. We hope to use this information to design new drugs that specifically target these invading cells.

GBM is a highly fatal cancer with little improvement in patient outcomes over recent decades. By using advanced AI to pinpoint the most aggressive and resistant parts of the tumor, we hope to develop new ways to predict patient outcomes and identify effective therapeutic targets for the most deadly cells of this disease.

Victor Ferreira, University Health Network (UHN)

Human cytomegalovirus (HCMV) is a common virus that remains dormant in the body after infection but can "wake up" (reactivate) in people with weakened immune systems. Lung transplant recipients are especially vulnerable to HCMV: up to 80% of those receiving a lung from a donor with prior HCMV exposure develop high levels of virus in their blood, and many progress to severe illness including direct infection and damage to the lungs (HCMV pneumonitis), which can damage the transplanted lung and threaten survival. Current prevention strategies, including prolonged antiviral medication, cannot fully stop reactivation and mitigate disease, and come with harmful side effects the longer they are used. 

This project will uncover the mechanisms leading to HCMV reactivation and development of disease in lung transplant recipients, aiming to develop better prevention and treatment strategies. 

First, we will identify which cells in donor lungs carry dormant HCMV and study how local inflammatory cues trigger its reactivation. 

Second, we will track patients' immune responses, particularly HCMV-specific T-cells, over time to find patterns that predict who will develop disease. 
Finally, we will use advanced single-cell RNA sequencing to pinpoint exactly which blood and lung cells contain HCMV during infection, and how the virus disrupts their normal function. 

By combining virology, immunology, and cutting-edge sequencing, this work will generate new tools to identify high-risk patients early, tailor antiviral use, and explore targeted treatments, such as removing virus-harbouring cells from donor lungs before transplant. Ultimately, these findings could improve lung transplant survival, reduce drug toxicity, and provide insights relevant to other transplant and immunocompromised patients worldwide. Our integrated approach offers the first comprehensive map of viral, immune, and inflammatory drivers of HCMV disease in this setting, paving the way for precision medicine solutions.

Joanne McLaurin, Sunnybrook Health Sciences Centre

We're working on a new gene therapy that could help restore lost brain function due to neurodegenerative diseases. Our goal is to make key progress in developing this therapy by reaching important research and product milestones. We plan to expand our intellectual property (IP), strengthen our regulatory approach, and make sure we're ready to attract investment and partnerships for clinical development. At the same time, we'll create a new spin-off company to drive the commercialization of this technology, ensuring it benefits both the health and economy of Canadians. 

Our gene therapy platform, developed at Sunnybrook Research Institute and the University of Toronto, targets a wide range of brain diseases. It works by reprogramming certain brain cells (called astrocytes) to become a new type of neuron. This process helps reduce harmful inflammation, supports the survival of brain cells, and creates new brain circuits to restore function that was lost due to disease or injury. 

We've received over $2 million in funding, which has helped us gather strong data in lab studies and in animal models of diseases like eye disorders, stroke, AD, and ALS. With this solid foundation, we're now ready to push two key products forward into the next stages of development and prepare them for clinical trials. With support from CIHR CMZ funding, we aim to bring both products to a point where they're ready for human clinical trials (IND ready). This will set the stage for attracting the investment and partnerships needed to move forward with clinical trials. 

The potential health impact is huge: approximately 1.5 million Canadians suffer from degenerative eye diseases, and around 1.65 million Canadians live with dementia, stroke, or ALS. Successfully developing these gene therapies will provide new treatment options for these patients, boost Canada's biotechnology sector, and offer health benefits worldwide.

Ming-Sound Tsao, University Health Network (UHN), (with Co-principal investigator Housheng He)

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Lung adenocarcinoma (LUAD) is the major subtype with a low survival rate. 

Tremendous efforts on integrated molecular profiling, including genomics, transcriptomics, epigenomics and proteomics have been made to understand genetic, genomic and epigenetic changes that drive LUAD development and progression. 

In contrast, post-transcriptional regulatory mechanisms, which also play critical roles in gene expression and tumor progression, have been relatively underexplored. To address this gap, our group has developed a robust and sensitive method to profile N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, in human tumors. m6A influences RNA stability, splicing, translation, and localization, and emerging evidence suggests it plays an important role in cancer pathogenesis. 

We propose to apply our method to systematically analyze m6A RNA modifications in primary and metastatic LUAD specimens. This approach will enable us to identify novel post-transcriptional regulatory mechanisms, uncover new biomarkers, and explore potential therapeutic targets that could ultimately improve clinical outcomes for lung cancer patients.

Rahul Gopalkrishnan, University of Toronto, and Amol Verma, Unity Health Toronto, (with Co-principal investigators Lauren Lapointe-Shaw, Aaron Jones, Fahad Razak and Surain Roberts)

When older adults' needs exceed the care available, this can trigger an emergency department visit, and then a hospital admission, all for the purpose of setting up supports at home. The term "social admission" is often used to describe hospitalization for the primary purpose of discharge planning rather than to treat an acute medical problem.

As Canada's older adult population grows quickly, pressure on hospitals for social admissions will rise. With the overall goal of supporting older adults to remain in their homes, this project will develop tools to identify social admissions. This will allow us to learn about older adults' care before, during and after social admission, identifying care gaps and promising strategies. 

Learnings from this project will allow for a more complete picture of the link between hospital and community sectors, to support health system planning and performance.

Rod Bremner, Sinai Health

Mutations in oncogenes and tumor suppressor genes cause cancer. However, these mutations are harmless in most cell types. Work on how cells evade cancer focuses on cell death, senescence or immune clearance. However, human tissues have many cells with "cancer-causing" mutations that never cause cancer, and these cells are not dead, senescent, or under immune attack, but function normally. Even in mice where half of all cells carry "cancerous" mutations, few cell types generate cancer, and the rest function normally. 

How do hundreds of cell types and trillions of cells resist cancer? Recently, we exposed a distinguishing feature of cancer-prone cells. While many cell types divide aberrantly when exposed to a cancer-causing mutation, the cancer-prone cells divide faster. This was true across tissues and mutations. Modestly slowing division blocked cancer, and although a mutated tissue retained other cancer hallmarks, there were zero tumors. Thus, division rate in mutated cells determines cancer susceptibility. Why is that the case? Normal division is fastest in the embryo and slows as tissues develop, and there are also more active genes/cell in embryonic cells. 

Now, we have discovered that cancer-prone cells have more active genes/cell than resistant cells. We hypothesize that faster division in mutated cells causes more active genes/cell, increasing the chance of accidentally creating an active gene combination that transforms a mutated cell into cancer. 

We will use in vivo models to test whether it is generally true that cancer-prone cells have more active genes/cell than cancer-resistant cell types, and to test if factors that control gene activation influence cancer incidence. To develop drug screening platforms, we will assess whether division rate and the frequency of active genes/cell also predict cancer susceptibility in vitro. 

Our work could explain cancer susceptibility and expose new ways to reduce cancer incidence.

Peter Dirks, Hospital for Sick Children (SickKids)

Glioblastoma (GBM) is an incurable brain cancer of children, adolescents, and adults. Despite detailed genomic maps of these tumours, there remains limited understanding about how normal brain cells become transformed into lethal cancer cells. 

Although genetics are critically important, we have found that the influences from the microenvironment can push dormant pre-cancerous cells into fully cancerous brain tumours. Specifically, we have found in data that forms the foundation of this proposal, that the neurochemical milieu of the brain, particularly the neurotransmitter dopamine (DA), plays a profound role in the formation of GBM in a mouse model. 

DA is made in the brainstem and then projects to each half of the brain, especially to an area called the striatum. When we ablate the DA signalling system to one side of the brain, we find that GBM tumours no longer arise in the striatum on that side. Therefore, for GBM to occur in the striatum, DA must be present. 

In this proposal we will extend these striking observations to determine whether inhibition of DA production or DA signalling is a promising treatment for GBM. We will test DA enhancing and inhibiting drugs on the formation and growth of brain tumours that arise in genetic models in mice. We will also test if the same drugs affect human GBM growth after they are transplanted into the brains of mice. We will then determine how precise modification of DA in the neural microenvironment influence GBM-genesis and growth in both mouse and human cells. To do this we will use classical neuroscience approaches and neural pathway specific ablation to determine how these brain-specific environmental changes influence the genesis and propagation of these tumours. 

As many drugs that modify DA have been developed by drug companies for chronic use for in a variety of human nervous system disorders, we expect that our findings could lead to their rapid deployment GBM treatment or even prevention.

Sascha Drewlo, Sunnybrook Health Sciences Centre

Every pregnancy carries risk. The most serious complications, including preeclampsia and fetal growth restriction, arise from placental dysfunction. When the placenta develops abnormally, it can threaten the health of both mother and baby, often leading to preterm birth and long-term health consequences. 

Current screening detects these problems only after they are established, leaving little time for effective intervention. We are developing a non-invasive, first-trimester test to detect placental dysfunction months before symptoms appear. 

This approach analyzes cervical extravillous trophoblasts (cEVTs), rare placental cells naturally shed into the cervix and collected safely during routine prenatal care. Using high-dimensional molecular profiling, including CyTOF, we will define early molecular changes in these cells and validate predictive signatures in a high-risk pregnancy cohort. 

Early detection in the first trimester will allow healthcare providers to offer targeted interventions at the most effective time, reducing complications and improving outcomes for mothers and babies.

Estelle Gauda, Hospital for Sick Children (SickKids), (with Co-principal investigators Agostino Pierro, Brian Kalish, Richard Keijzer, Martin Offringa, Prakeshkumar Shah and Kevin Thorpe)

Necrotizing enterocolitis (NEC) is a life-threatening disease that affects the intestines of mostly preterm and sick newborns. Despite the best available care, many infants with NEC do not survive, and those who do may face long-term health challenges. There is currently no treatment that can stop NEC once it starts. 

Our team has developed a promising new approach called remote ischemic conditioning (RIC), which involves gently inflating and deflating a small blood pressure cuff on a baby's arm or leg to boost blood flow and protect the intestine. We have already shown that this method is safe in previous studies, including an international trial that is nearly complete and has shown no side effects. We are now ready to test whether RIC can improve survival in a large group of babies with NEC. 

This Canada-led study will include hospitals around the world and has been designed with input from parents to ensure it is family-centered and focused on what matters most-saving lives and improving outcomes for the most vulnerable newborns.

Ana Konvalinka, University Health Network (UHN)

Kidney transplantation is the best treatment for end stage kidney disease. However, most kidneys fail prematurely. The main cause of premature graft loss is antibody mediated rejection (AMR). Unfortunately, there are currently no effective treatments for AMR, and we do not have adequate markers to tell us who is most at risk for losing their graft. 

We recently identified a group of proteins in the kidneys with AMR that accurately predict graft loss and are linked to the complement pathway. Our goal is to identify the places in the kidney where these proteins are made, and to demonstrate that measuring these specific proteins in the correct kidney location can predict who will lose their graft and how to treat AMR better. 

First, we will test whether our proteins of interest, measured in kidney graft biopsies, predict graft loss in two international cohorts of kidney transplant recipients. We will next use an innovative method called imaging mass cytometry to determine where in the kidney our proteins of interest are expressed. Lastly, we will examine if our proteins of interest are decreased after successful treatment of AMR.

We expect to find that our proteins of interest are most highly expressed at the sites of immune injury in the kidneys with AMR. We also expect that these proteins will predict kidney graft loss in new cohorts of patients with AMR. Lastly, we expect that our proteins will decrease following treatment of AMR only in those patients whose grafts remain functional. Based on these findings, we will be able to finetune current and propose novel treatments for AMR. 

Our project will determine who is most at risk for kidney graft loss, at the time of AMR diagnosis. We will improve the lives of patients, because we will identify potential ways to monitor and treat AMR. In the future, we will translate these tests into clinical trials to prevent premature kidney transplant loss.

Marco Magalhaes, Faculty of Dentistry

The mouth is a unique environment, constantly exposed to bacteria, saliva, and the body's natural defense systems. These systems typically work in harmony to maintain our health. However, sometimes the cells that line the mouth (keratinocytes) undergo changes, known as oral dysplasia or potentially malignant lesions, which can, in some cases, progress to oral cancer. Oral cancer is a severe disease with high rates of illness and death. Finding better ways to predict and prevent the development of oral cancer is critical, and this application focuses on novel aspects related to oral cancer progression. 

Our research has identified a molecule called Fn14 (fibroblast growth factor-inducible 14 or TNFRSF12A) that plays an important role in this process. We have discovered that Fn14 activity increases significantly as oral lesions progress toward cancer, both in human samples and in animal models. We believe Fn14 helps abnormal cells move and invade surrounding tissues, making it easier for cancer to develop. 

To test this idea, our project combines animal studies, laboratory experiments, and patient samples. In mice that lack Fn14, we will study whether cancer develops differently. In the laboratory, we will explore the chain of signals that cause Fn14 to rise and drive cell invasion. Finally, by analyzing tissue from patients with precancerous mouth lesions, we will determine whether higher levels of Fn14 predict which lesions are more likely to become cancer. 

If successful, this research will reveal a new biological pathway that contributes to the development of oral cancer. More importantly, it may provide health care providers with a way to identify patients at greater risk earlier, improving how we monitor, diagnose, and treat people with precancerous lesions in the mouth.

Mario Ostrowski, Unity Health Toronto

Antiretroviral therapy treatment (ART) has greatly prevented the clinical progression outcome of HIV infection by suppressing plasma virus levels to below the detection limit. However, ART does not cure because it does not eliminate the persistence of a small pool of infected CD4+ T cells (also known as latent reservoir) that harbour replication competent virus that can persist indefinitely in people living with HIV (PLWH)- leading to viral rebound when treatment is interrupted. The main immune cell that can kill HIV infected cells is called the cytotoxic CD8+ T cell or CTL. PLWH usually have low functionality of their CTLs, for various reasons. However, there are a few PLWH, called elite controllers who have such potent CTLs that they force the virus into a deeply latent state. 

We propose that if we can induce a similar 'state' in other PLWH, this would be a functional cure that would not require ARTs- a key step in helping eradicate HIV reservoir. 

Our study will use state-of-the-art techniques to determine whether we can make CTLs taken from PLWH, reduce or eradicate the reservoirs in the laboratory.

Nadine Shehata, Sinai Health

PANDA: Prevention of Anemia in Pregnancy (with Co-principal investigators Rohan D'Souza and Sabrina Kolker)

Around half of pregnant women develop anaemia caused by lack of iron. This can lead to increased risks for both mother and baby during pregnancy and childbirth. Treating anaemia after it develops does not reduce all the risks, thus anemia should be prevented. 

PANDA is a large international study led by researchers in the United Kingdom that will help us to understand all the effects for women and babies if we give low-dose iron supplements during pregnancy to prevent anaemia, such as babies being born early. To do this we will participate in this study, in which 11,020 women will be allocated by chance to receive either iron tablets or placebo (an inactive tablet that looks like an iron-tablet) during their pregnancy and up to six weeks after childbirth. 

We plan to include 1,080 Canadian patients from three hospital sites in Ontario over three-year period. There are 30 other sites participating in the United Kingdom. 

If low dose iron does not improve pregnancies, costs can be saved by not screening pregnancies routinely for iron deficiency.

LEAP: Low molecular weight hEparin vs. Aspirin Postpartum, a multicenter pilot RCT (with Co-principal investigators Evangeli Vlachodimitropoulou Koumoutsea, and Marc Carrier)

Pregnancy involves many changes to support the growing baby, but these changes also increase the chance of forming blood clots (venous thromboembolism, or VTE).

Women who have already had a blood clot are at especially high risk of having another clot in the weeks after giving birth. Many guidelines currently recommend daily injections of low molecular weight heparins (LMWHs) for six weeks postpartum to prevent blood clots, as they are safe for breastfeeding. However, these recommendations are mostly based on expert opinion rather than on evidence from high-quality studies, and daily injections can be uncomfortable, costly, and result in bruising and bleeding. 

Aspirin (ASA) is a widely available, low-cost medication that has been used for many years to help prevent blood clots in different conditions. It is generally well-tolerated, can be used while breastfeeding, and does not require injections. If switching from a six-week course of LMWH to a shorter course of LMWH followed by ASA is proven to be equally safe and effective, it could reduce the burden of treatment for many new mothers. 

To answer this question, we plan to include 90 patients across four Canadian centers in this pilot study. If the results show that the shorter treatment is safe and feasible, a larger, definitive study will follow including the 90 patients that will be recruited in this study. 

Ultimately, if our findings are confirmed, this result would spare many women the inconvenience of extended daily injections, while still protecting them from the dangerous complications of blood clots.

Jeremy Sivak, University Health Network (UHN)

Neurodegeneration involves a complex sequence of biochemical signals. Yet, to date common approaches to promote neuron survival have not been successful clinically. 

Using an alternative approach, we identified potent support signals for neurons that are controlled by a small lipid molecule called lipoxin B4 (LXB4). We showed that LXB4 acts to directly protect neurons and is highly effective in models of retinal neurodegeneration relevant to the common blinding disease, glaucoma. Yet, the chemical properties of LXB4 itself make it unsuitable to use as a drug. Therefore, identifying its downstream cellular receptor and signals will define a potent new neuroprotective pathway and new therapeutic targets. 

Using a series of chemical and genetic tools we have identified a candidate receptor and performed initial validations to study its interaction with LXB4. Here, we will profile this protective signalling and pursue strategies to promote this protective effect in models of retinal neurodegeneration. Together, this work will demonstrate the potential to exploit this pathway as a new therapeutic strategy.

Darren Yuen, Unity Health Toronto (with Co-principal investigators Eno Hysi and Michael Kolios)

Affecting one in every 10 Canadians, kidney disease is a major public health problem. Kidney transplantation restores kidney function and can greatly improve lifespan and quality of life. Unfortunately, transplant kidneys often become injured over time, with inflammation and scarring being two forms of damage that commonly occur. Currently, the only way to measure transplant kidney inflammation and scarring is by a painful biopsy. 

Our team is developing a new bedside ultrasound technology that can "see" the scarring and inflammation in transplant kidneys using safe, easy-to-perform ultrasound scans. By adding special bubbles and advanced computer analysis, we can detect kidney damage early, track how it changes, and help doctors choose the best treatments-without the need for a biopsy. 

This breakthrough could make kidney care safer, more accurate, and more personalized for patients everywhere.