LSI researchers awarded funding in Fall 2025 CIHR Project Grant competition

Congratulations to all LSI researchers who received funding through the Fall 2025 CIHR Project Grant competition! A list of PIs and summary of the funded projects is provided below. In total, these grants were awarded $5.3 million from this competition.

Investigator: Sarah Hedtrich

In Situ Gene Editing to Rescue Genetic Skin Diseases

Co-investigators: Eric Jan

Certain genetic mutations cause rare skin conditions like Epidermolytic Ichthyosis (EI) and Harlequin Ichthyosis (HI), as well as common diseases like atopic dermatitis (AD). These diseases often lack effective treatments, leaving patients with significant challenges. Gene editing, a groundbreaking technology, has the potential to correct these mutations and provide lasting cures. However, delivering gene-editing tools directly to the skin and targeting the right cells remains a significant challenge. This research aims to develop innovative, topical gene-editing therapies to address these unmet needs. The project focuses on three goals: (1) designing strategies to correct genetic mutations responsible for EI, HI, and AD, (2) optimizing messenger RNA (mRNA) molecules to work specifically and effectively in skin cells, and (3) creating lipid nanoparticles (LNPs) that can deliver gene-editing tools directly to skin stem cells. Using advanced technologies, the team will refine mRNA designs to improve how they interact with human skin and enhance the precision of gene editing. By targeting skin stem cells, the approach aims to offer long-lasting and potentially curative treatments. If successful, this work will pave the way for new therapies for severe genetic skin diseases and conditions like atopic dermatitis, transforming care for patients with few or no current options.

Investigator: Eric Jan

Translation initiation via factorless internal ribosome entry site mechanisms

Proteins are expressed from a viral RNA. Some viruses such as poliovirus and Hepatitis C use a translation mechanism called an Internal Ribosome Entry Site or IRES for expressing their proteins. This IRES mechanism is not only important for viruses but also for cellular genes, including those involved in cancer. Therefore, elucidating IRES mechanisms is crucial for understanding a fundamental process of gene expression. Currently, IRES mechanisms are poorly understood. To gain insight, we will characterize a novel IRES mechanism found in an insect virus, called dicistrovirus. Using biochemical techniques, we will identify how this IRES interacts with and hijacks the host cell machinery. This insect IRES is functional in many systems including yeast and human cells, indicating that this unprecedented mechanism is conserved and that specialized cellular genes may also use this mechanism. Using biochemical methods, we will elucidate key elements that govern IRES mechanisms. Moreover, we will identify key viral proteins that promote IRES gene expression. Finally, using this knowledge, we can search for cellular genes that also use this mechanism for gene expression. This proposal will not only shed light into the biological significance of this novel viral IRES mechanism but also provide a framework for understanding other viral and cellular IRES mechanisms in general.

Investigator: Kenji Sugioka

Elucidating the Mechanism and Function of Cortical Flow in Wnt-dependent Asymmetric Cell Division

Dr. Sugioka was also awarded a PRIZE – Project Grant – PA: Prize: Early Career Investigator in Cancer

When cells divide, they not only multiply but also determine their position and orientation within the body-a process crucial for proper development. If this process goes wrong, it can lead to diseases such as cancer and congenital disorders like microcephaly. This project focuses on cytokinesis, the final step of cell division when a single cell splits into two. While much research has explored earlier stages of cell division, how cytokinesis itself becomes asymmetric remains poorly understood. Recent evidence suggests that cortical flow-the movement of a motor protein called myosin across the cell surface-helps control this asymmetry. Interestingly, we have discovered that Wnt signaling, a key pathway involved in human diseases such as colon cancer, regulates cortical flow during cytokinesis. However, how Wnt signaling achieves this control remains unknown. To investigate this, we will use embryos from the tiny roundworm Caenorhabditis elegans, a model organism that shares many of the same cell division mechanisms as humans. Using advanced microscopy, genetic techniques, and mathematical simulations, we will analyze how cortical flow and Wnt signaling work together to break symmetry in cell division. Understanding this fundamental process will not only advance our knowledge of cell division and Wnt signaling but may also provide insights into potential treatments for diseases caused by defects in asymmetric cell division, including cancer.

Investigator: Kenji Sugioka

Elucidating the Role of Adhesion in Actomyosin-dependent Establishment of Animal Laterality

Our bodies may appear perfectly symmetrical from the outside, but internally, our organs are arranged asymmetrically in ways that are essential for their proper function. About 1 in every 10,000 children is born with a condition called a laterality defect, in which this left-right organization of organs is disrupted. These defects can lead to serious problems-such as an abnormally looping heart, blocked bile ducts, or a misplaced spleen-that often require lifelong care. The process that establishes left-right differences begins very early in development. Previous studies have identified around 40 genes involved in this process, many of which are linked to key cell signaling pathways and tiny hair-like structures on the cell called cilia. However, these genes account for only 15-20% of lateralit defects, leaving the majority of cases unexplained. Recent research suggests that another group of proteins, known as actomyosin regulators, may also play a crucial role. These proteins control cell movement and shape and are essential for establishing left-right differences in many organisms-yet they have not been studied as extensively as cilia. In our project, we will take advantage of the genetic tractability and short lifespan of the tiny worm Caenorhabditis elegans to investigate how actomyosin proteins establish left-right organization during development. By combining genetic, cell biological, and biophysical approaches, we aim to identify new genes and uncover the mechanisms by which a cell's inherent "handedness" is generated and translated into the large-scale organization of the body. Ultimately, this research may help explain cases of laterality defects that remain a mystery today.

Investigator: Hilla Weidberg

Understanding the role of Mge1's targeting sequence in mitochondrial stress signaling

Mitochondria are the powerhouses of the cell, acting as factories that produce energy and sustain cellular metabolism. Given their central role, mitochondrial function is crucial for organismal health. Indeed, when mitochondria become dysfunctional, they can contribute to a range of diseases, including neurodegenerative disorders such as Parkinson's and Alzheimer's. To counteract mitochondrial damage, cells activate protective programs that detect and restore mitochondrial function. A common consequence of mitochondrial dysfunction is the improper delivery of proteins that are meant to enter these organelles. When proteins accumulate outside mitochondria, they act as distress signals, alerting the cell to potential damage. Understanding how these proteins function as messengers may provide new opportunities to enhance the cell's protective responses and improve resilience against disease. Our research has recently identified a novel protective program that promotes mitochondrial recovery. We discovered that a small, unique region of a mitochondrial protein plays a key role in activating this program. Under normal conditions, this region facilitates the transport of the protein into mitochondria. However, when blocked from entering the mitochondria, it adopts a different function-signaling mitochondrial stress. Our goal is to further investigate how this region enables communication between mitochondria and the rest of the cell to trigger protective responses. By uncovering fundamental mechanisms that detect and respond to mitochondrial dysfunction, our work has the potential to inform the development of therapeutic strategies aimed at enhancing cellular resilience. These insights may contribute to new approaches for treating neurodegenerative and other diseases associated with mitochondrial impairment.

Investigators: Mypinder Sekhon, Mark Cembrowski (LSI), Donald Griesdale, George Isac

Multimodal Neuromonitoring during Normothermic Regional Perfusion in Organ Donors Determined Dead by Circulatory Criteria following withdrawal of life sustaining measures

In Canada, there is an urgent need to increase the availability of organ donation opportunities and improve the quality of available grafts to optimize transplant outcomes. Despite the clear expansion and improvement of organ donation and transplantation practices in Canada, Canadians continue to die on transplant waiting lists. Death must occur prior to vital organ donation for eligible donors, which is the foundation of the "dead donor rule". In the setting of donation after circulatory death (DCD), withdrawal of life-sustaining measures (WLSM) is undertaken and organ donation commences after death. While the emergence of DCD has increased organ donation, a greater duration of warm ischemic time between WLSM and death determination is associated with poor graft function and outcomes in transplant recipients. A post-mortem strategy of initiating extra-corporeal membrane oxygenation (ECMO) after death determination has been championed as an effective strategy to mitigate and reverse the harmful effects of warm ischemia on the eligible grafts. Although effective, concerns have been raised that this technique could invalidate death determination by reperfusion of the brain. As such, using comprehensive neuromonitoring, we aim to evaluate the presence or absence of brain function and perfusion during post-mortem ECMO. Demonstrating absence of both would add credence to the adherence to the dead donor rule, increase heart donation opportunities and improve graft viability for other visceral organs by mitigating warm ischemia pathophysiology in the donor.

Investigator: Scott Tebbutt

Multi-omics plasma biomarkers for early detection of cardiac allograft vasculopathy in adult heart transplant recipients

Co-investigators: Leonard Foster (LSI), Tao Huan, Mustafa Toma, Chengliang Yang

Heart transplantation (HTx) is a life-saving surgery for patients with end-stage heart failure. A major complication is cardiac allograft vasculopathy (CAV), a condition in which the arteries of the donated heart gradually narrow, increasing the risk of heart failure, graft loss, and death in the recipient. CAV often develops silently and is usually detected only after irreversible damage has already occurred. Currently, diagnosis relies on invasive procedures such as coronary angiography or intravascular ultrasound. These tests are expensive, uncomfortable, and not practical for regular monitoring. A simple blood test to detect CAV earlier would allow for timely intervention and may help prevent disease progression. This project aims to develop such a blood test using metabolomics and proteomics, which measure molecules and proteins in blood to reveal early biological changes before symptoms appear. We will analyze stored blood samples from HTx patients who later developed CAV and compare them to matched patients who remained healthy. Specifically, we will: 1) analyze early post-HTx samples (60-180 days) to identify metabolic markers that may predict future CAV; 2) validate 18 protein markers previously discovered by our team; 3) examine how all of these markers change over time using serial samples collected during the first year after HTx, to see whether patterns predict risk; 4) assess how well these markers detect disease at the time of standard diagnosis; 5) combine metabolite and protein data to build a predictive model for early detection. This study will use samples from the HEARTBiT cohort, a multicentre study of HTx patients led by Dr. Tebbutt. All samples are already collected and stored in a secure hospital biobank. If successful, this work will support the development of a simple, accurate blood test to detect disease early, improve patient care, reduce the need for invasive procedures, and ultimately improve survival and quality of life after HTx.