CIHR-IG Research Spotlight (2025)

Dr. Timothy Audas

Associate Professor, Simon Fraser University

Alzheimer's disease and dementia are emerging public health epidemics that affect nearly a million Canadians. While the symptoms can be highly variable, a common feature in these patients is the formation of large protein plaques/clumps that can damage brain tissue. For years, these types of plaques were thought to be indestructible and only found in patients suffering from neurodegenerative diseases. However, our lab has recently found that similar plaques can naturally form during periods of stress, and that cells possess an efficient disassembly machinery, which we may be able to re-purpose to break down the disease-associated protein aggregates.

Our CIHR-funded study explores how and when natural plaques assemble and disassemble. We have found that several prominent cellular chaperones act as potent plaque disassembly factors following periods of stress. Normally, these chaperones float around the cell assisting in the construction of cell components, but upon stress exposure these chaperones are modified to make them highly efficient plaque disassembly factors. In the future, we will be looking to see how modification of these chaperones is controlled, and whether dysregulation of these factors could drive Alzheimer's disease progression.

We believe that this could be the first step in developing new therapeutic strategies that will bring relief to patients struggling through this silent epidemic.

Funded project: Characterizing the Cellular Mechanisms that Regulate Physiological Amyloid Disassembly

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Dr. Yuè Li

Assistant Professor, School of Computer Science, McGill

Major Depressive Disorder (MDD) remains a leading cause of disability worldwide, yet its molecular underpinnings are poorly understood. Dr. Yuè Li's team at McGill University is using single-cell genomics and artificial intelligence (AI) to uncover how gene regulation differs in the brains of people with and without MDD. By analyzing the transcriptomes and epigenomes over 160,000 brain cells, the project will link genetic control regions to disease-related genes, map how cellular organization and interactions differ across brain layers and between sexes and predict the effects of genetic variants thereby deciphering the disease genome. Experimental validation will validate predicted regulatory regions in the genome, driver mutations, and causal genes.

Dr. Yuè Li's team has developed powerful AI-driven tools to uncover how gene regulation differs in the brains of people with depression. The team's AI model successfully aligned gene expression and chromatin data from individual nuclei, revealing biologically meaningful cell-type patterns that highlight how gene control is disrupted in MDD.

Building on these advances, we are now applying "genome language models" to predict how genetic variants alter gene activity and will validate key findings in the lab using CRISPR-based experiments. These integrated approaches will generate a comprehensive molecular map of depression—linking DNA variants, regulatory elements, and spatial brain architecture—to guide future development of precision therapeutics for mental health disorders.

Funded project: Single-cell multi-omic integration and gene regulatory network inference towards personalized psychiatry for major depressive disorder

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Véronique Boumtje

Doctoral trainee in Molecular Medicine, Québec Heart and Lung Institute (IUCPQ), Université Laval

Lung cancer remains the leading cause of cancer-related deaths, partly because existing screening programmes are unable to detect more than 10% of cases. Candidates for screening are currently selected based solely on demographic and behavioural criteria, ignoring the genetic component of lung cancer, which has been recognized for decades. We develop and use polygenic risk scores (PRS) to predict and diagnose lung cancer early, and these have been proven to be effective in identifying genetic risk at individual and population levels.

At the individual level, PRS have shown that people with a high genetic risk of lung cancer are almost 20 times more likely to develop the disease if they smoke or have smoked, compared to people with a low genetic risk who have never smoked.

At the population level, PRS offers a tangible net benefit in high-risk screening cohorts but has limited added value in larger populations with robust clinical models. Our results suggest that PRS should be used selectively to reduce unnecessary additional testing and improve early detection rates in lung cancer screening programs.

Funded project: Développement et utilité clinique du score de risque polygénique en cancer du poumon

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Dr. Mohan Babu

Professor and Chancellor's Research Chair in Network Biology, University of Regina

How Energy-Producing 'Cell Batteries' May Shape Bipolar Disorder

Bipolar Disorder (BD) affects more than 2.8 million Canadians and causes mood swings, from depression to mania, as well as problems with thinking and memory. Its causes are still unclear, but studies show that mitochondria – the energy-producing parts of our cells – do not work properly in people with BD. Current treatments improve mitochondrial function, but it is still unknown how these drugs work at the molecular level or which mitochondrial proteins are involved.

With CIHR funding, Dr. Mohan Babu and collaborators from the Universities of Saskatchewan and British Columbia and Dalhousie University compared neurons (nerve cells) grown from people with and without BD. In healthy neurons, groups of proteins that support energy production, metabolism and communication between cells worked as expected. In BD neurons, many of these protein groups were disturbed, suggesting that problems in mitochondrial "machinery" play a direct role in BD. They found that some existing antipsychotic medications may help restore these protein groups and rebalance mitochondrial function.

The team also examined a common feature of BD – neuronal hyperexcitability, where brain cells fire excessively. They identified several compounds that reduce neuronal hyperactivity, in part by acting on mitochondrial gene targets. Now, they aim to understand how these genes affect brain cell communication in BD. They will also determine which mitochondrial pathways are most affected in BD and focus on the most promising mitochondrial targets for future treatments.

Funded project: Deciphering Mitochondrial Interplay in Bipolar Disorder

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