LSI researchers awarded funding in Spring 2026 CIHR Project Grant competition

Congratulations to all LSI researchers who received funding through the Spring 2026 CIHR Project Grant competition! A list of PIs and summary of the funded projects is provided below. In total, these grants were awarded $8.8 million from this competition.

Investigator: Yossef Av-Gay

Developing fenoxacrim derivatives against drug resistant Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) cause serious infectious disease such as TB, that kills nearly 2 million people annually. Mycobacterial infections are notoriously resistant to the existing antibiotics and often require combination of 3 or more antibiotics to eradicate. This underscores the need for new drug development. In this research work, we plan to develop a potent antibacterial compound against Mtb. This compound will be based on fenoxacrin, an antimicrobial we have identified in an earlier screen of compounds library against Mtb and other bacterial infections. Fenoxacrim showed potent activity against both drug-susceptible and drug-resistant clinical isolates of Mtb as well as high selectivity to the pathogens over mammalian cells making it suitable for further development. To understand the structural features required for its antibacterial potency and selectivity over mammalian cells, we synthesized different analogues of fenoxacrim and figured out the part of its chemical structure that could be modified to improve potency and selectivity. As such, more analogues with much enhanced potency and selectivity were generated. Preliminary work we conducted to study the mode of action of fenoxacrim showed it targets a key bacterial specific enzyme required to synthesize cell wall, known as undecaprenyl pyrophosphate synthase enzyme (UPPS). Notably, UPPS is a novel target that is not targeted by any of existing clinically approved antibacterials. The main aim of this research project is to advance fenoxacrim and its synthetic analogues by (i) further modifying its chemical structure to make a new drug candidate that is more potent, safe and suitable for oral administration, (ii) to conduct further studies to confirm UPPS as a target and study the detailed mode of action (iii) assess toxicity and efficacy of the best candidate in animal infection models. The ultimate outcome will be generation of a new drug candidate ready for clinical use.

Investigator: Phillip Domeier

Regulation of B cell memory establishment and recall by Thymic Stromal Lymphopoietin

Annual vaccines to influenza help reduce the spread and severity of flu, but effective protection depends on the generation of long-lived immune memory. Immune memory is established by many types of immune cells, including memory B cells, which can be recalled to produce protective antibodies that neutralize or block a recurring infection. Vaccination can establish pathogen-specific memory B cells without causing severe illness to establish this immune memory. However, despite the availability of vaccines, influenza is still a highly contagious virus that causes over 3,500 deaths in Canada each year. In addition to the limited duration of protection by influenza vaccines, some vaccine recipients fail to develop sufficient immune memory, and can develop severe disease. An immune signaling molecule called thymic stromal lymphopoietin (TSLP) acts on several different immune cells to modulate antibody production during inflammation. However, the role of TSLP and signaling by its receptor in regulating vaccine-induced immune memory has not yet been explored. In this study, we will investigate how TSLP receptor signaling modulates memory B cells after vaccination, and how TSLP signaling can be manipulated to modulate the establishment and recall ability of antigen-specific memory B cells. We hypothesize that TSLP signaling regulates both the generation and recall of memory B cells. This work has potential to help design better influenza vaccines that provide more potent or longer lasting protection. Furthermore, our findings could improve our understanding of TSLP and predict how TSLP targeted therapeutics could impact B cell responses.

Investigator: David Fedida

The structural basis of state-dependent potassium channel inhibition

During the human heartbeat cycle, the cells in the heart go from rest to fully active as the heart contracts and pumps blood, and back to rest again as the heart muscle relaxes. All this happens over a time scale of about one second. Underlying this pumping action of the heart is the electrical activity within the cells, coordinated by small proteins called ion channels. When this process goes wrong, serious arrhythmias (irregular and fast heartbeats) and even sudden death may result. Antiarrhythmic compounds can be used to control these dangerous heart rhythms and restore normal heart activity. In this study we will examine how different antiarrhythmic compounds bind to a protein ion channel, called KCNQ1, that is able to conduct potassium and has a vital role in maintaining the normal electrical activity of the heart, especially during the relaxing phase of the heartbeat. This ion channel is like a tiny machine that alters its structure in response to changes in the heart cell voltage. However, until recently we have not been able to study these structures as the ion channels are embedded in the fatty cell membranes that make them resistant to X-ray crystallography methods. Recently, though we have been using high resolution microscopy to visualize the channels in their different states during the cardiac cycle. We want to do this because an understanding of how specific compounds can bind to the distinct shapes that the ion channel protein makes as it goes from rest to activated and back again gives us critical information to design new and more specific drugs to modulate the ion channel activity and treat diseases such as long QT syndrome and atrial fibrillation. The studies will be complemented with computer simulations to gain a greater understanding of how the protein functions when exposed to ion channel modulating drugs, during all stages of the cardiac cycle.

Investigator: Arun John Peter

Mechanistic dissection of the lipid transporter Vps13 and its metabolic regulation at membrane contact sites

Lipids are essential building blocks of cells, forming the membranes that surround and organize cellular compartments. To function properly, cells must transport lipids from where they are made - primarily the endoplasmic reticulum - to other parts of the cell. How this transport occurs inside living cells remains a central unanswered question in cell biology. A group of proteins known as bridge-like lipid transport proteins are thought to move lipids directly between cellular compartments at sites of contact between them. In humans, defects in these proteins are linked to severe neurological disorders, highlighting their importance for normal cellular physiology. However, understanding how these proteins work inside cells has been challenging because we lack tools to directly measure lipid transport in living systems. To overcome this limitation, we have developed a new method called METALIC (Mass tagging-Enabled TrAcking of Lipids In Cells), which allows us to follow the movement of lipids inside living cells. In this project, we will use METALIC together with complementary approaches to uncover how the founding member of this protein family, Vps13, transports lipids and how its activity is regulated by the metabolic state of the cell. By revealing the basic principles that govern lipid transport between cellular compartments, this research will provide fundamental insights into cell organization and lay the groundwork for future strategies to address diseases caused by defective lipid trafficking.

Investigator: Emilia Lim

A single-cell spatial analysis of the impact of air pollution exposure on molecular pathways in lung cancer

Lung cancer is the leading cause of cancer death in Canada and worldwide. While smoking is the main risk factor for lung cancer, in the Western world, ~15% of lung cancers, and in Asia, >50% of lung cancers, occur in people who have never smoked. Exposure to air pollution is an emerging risk factor for lung cancer development, as 99% of people in the world live in areas where air pollution levels are above the WHO guidelines. However, it is unclear how most air pollutants promote cancer. My research has shown that black deposits from air pollution can promote cancer by making damaged lung cells grow and divide faster. We aim to build on these findings by studying how these pollution-associated deposits change the function of different types of lung cells. My ultimate goal is to find ways to prevent lung cancer. We will zoom into individual lung cells from tumours and normal lung tissue to examine how their association and distance from pigments influences their function. We expect that immune cells close to pigments will display characteristics associated with inflammation. This research will help find ways to prevent changes in our cells caused by pollution. Climate change and its impact on human health cannot be ignored. Wildfires are of increasing concern, and the emitted smoke continues to degrade our air quality. Thus, we urgently need to understand how air pollution promotes cancer development to reduce our risk of developing cancer.

Investigators: Matthew Lorincz

Molecular characterization of the neomorphic linker histone H1-4 frame-shift mutation pathogenic for Rahman syndrome

Each cell in an individual has the same genetic code, yet our body consists of many different cell types. This is a result of our cells intrinsic ability to turn genes on and off, depending on which genes are needed within that specific cell type. Genes are regulated in part by "epigenetic proteins" including histones, the proteins around which the DNA is wrapped, and the chemical marking of these proteins. The presence of the "linker" histone called H1 is known to influence the activity of enzymes that deposit these marks, and in turn the genes they control, by bringing other histones associated with DNA closer together in physical space. Interestingly, mutations within the gene that encodes linker histone H1.4 leads to the neurodevelopmental disorder (NDD) known as Rahman syndrome, while mutations in other genes that encode epigenetic enzymes are responsible for a number of NDDs with similar epigenetic and clinical outcomes, including Sotos and Weaver Syndromes. Disruption of any one of the genes encoding these proteins leads to a cascade of changes, disturbing the balance between epigenetic marks and in turn causing mis-regulation of other genes and eventually the relevant NDD. Understanding how these epigenetic enzymes and histone H1.4 work together to regulate other genes is crucial for understanding how mutations in H1.4 cause disease. We propose to study the impact of the Rahman Syndrome H1.4 mutations by: 1. identifying the proteins that interact with mutant versus normal H1 (using an approach called "TurboID"), and 2. using state-of-the-art genetic engineering to generate a cell culture system in which the mutant form of H1.4 seen in disease is produced and in turn we can study the epigenetic alterations occurring in neuronal cells in Rahman syndrome. We anticipate that this work will generate important molecular insights into the epigenetic pathways disrupted in Rahman Syndrome that will aid in the development of new treatments for this and related NDDs.

Investigators: Carolina Tropini

Impact of loss of commensal bacteria on enteric infection

Human health is intimately connected to our microbiota, a unique, constantly evolving consortium of trillions of bacteria that live in and on our bodies. Gut microbes produce compounds that are absorbed into our blood, providing nourishment, and affecting diverse functions such as digestion, immunity, neurodevelopment, as well as colonization resistance against invading and potentially harmful microorganisms, or "pathogens". Antibiotics have been shown to disrupt the gut microbiota and decrease its ability to protect the host against infection. Beyond antibiotics, it is not known what other microbiota disruptions may reduce colonization resistance. My lab has been investigating how microbiota disruptions and the loss of specific microbiota members affects infection by gut pathogens. In this project we will use a combination of cutting-edge experimental and computational techniques to study how pathogens infect and colonize the gut when certain microbiota species are lost. This work will also investigate microbiota therapies that can counteract the loss of species and increase microbiota diversity to promote resilience to infection, while identifying the mechanisms involved in microbiota resilience to pathogen invasion. This research will lead to a deeper understanding of pathogen infections and inform the development of new probiotic therapies that will benefit the health of millions of Canadians.

Investigators: Kenji Sugioka

PRIZE – Project Grant – PA: Maud Menten – Biomedical Research

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

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.

Blood tests capable of diagnosing Alzheimer's disease, the most common type of dementia, have been recently been approved for use in clinical practice. Although these blood tests are a major step forward in the diagnosis of Alzheimer's disease, they have several limitations. First, blood tests for other types of dementia, such as frontotemporal dementia, Lewy body dementia, and vascular dementia, still need to be developed. Second, the current tests cannot accurately identify the stage of Alzheimer's Disease a particular patient is in. Third, existing tests do not predict future cognitive decline. Thus, this study aims to develop new blood tests for different types of dementias. This will be done by measuring 220 proteins in a single blood sample using a new and highly sensitive technology. To determine which proteins detect specific pathologies, we will measure blood samples from participants whose brains have already been examined at autopsy and have been classified into the different pathological types listed above. By comparing across groups, we will see what blood proteins are changed in each pathological group. We will then measure these biomarkers in participants at different stages of cognitive impairment and dementia to determine at what point we start to see changes in biomarkers to improve early detection and disease staging. Finally, we will determine whether there are biomarkers that can predict how quickly cognitive problems get worse. Development of such blood tests will improve the diagnosis of multiple types of dementia even early in disease course, which will greatly aid in developing new targeted treatments for dementias.