From left to right : Jennifer Estall, Hua Gu, Artur Kania, Marlene Oeffinger, Rémi Rabasa-Lhoret and Eric Racine
The Montreal Clinical Research Institute (IRCM) is proud to announce the success of its researchers in the 2024 Fall competition of the Canadian Institutes of Health Research (CIHR) Project Grants program. Six grants were awarded to its researchers, reaching a 25 % success rate, way above the national average for this competition.
Congratulations to scientists Jennifer Estall, Hua Gu, Artur Kania, Marlene Oeffinger, Rémi Rabasa-Lhoret and Eric Racine, who will benefit from nearly $4.7 million in total, to further their work aiming to improving therapies and understanding for burning health issues. In addition, our scientists May Faraj and Jean-François Côté will contribute to projects led by colleagues from McGill University, who will also receive funding resulting from this CIHR competition.
“Behind these grants lies long-term work on several diseases, which depending on whether they are funded or not, will translate more rapidly into innovative therapies or, be slowed down in achieving their beneficial results,” emphasized Dr. Jean-François Côté, President and Scientific Director of the IRCM, adding: “At a time when science is fragile on many levels, the importance of investing in research cannot be ignored. A warm thank you to CIHR for their invaluable support.”
ERIC RACINE (with the participation of Hugo Chapdelaine, Rémi Rabasa-Lhoret and Bénédicte D'Anjou):
Living laboratory of citizen ethics and co-creation of deliberative spaces for and by people with chronic or rare conditions.
Summary: Ethical problems undermine the values that guide our individual lives, our social relationships and the functioning of our institutions. If left unresolved, these problems can cause a great deal of distress and damage the working climate and interpersonal relationships. People with chronic or rare illnesses experience ethical problems in which their values are flouted. The aim of this research project is to develop support and resources designed for and by sufferers in the form of a “living lab”, an innovative participatory research method in which those affected by problems are involved in understanding the problems and finding and implementing solutions.
ARTUR KANIA
The molecular specification of somatotopic organization in the rodent spinal cord
Summary: Somatotopy is an organizational principle of neural circuits where the relative positions of many neurons in our nervous system reflects the anatomical organization of the body. The most famous example of this was demonstrated by the Canadian neurologist, Dr. Wilder Penfield, in the part of the human brain that receives information about the surface of our skin. There, for example, neurons that subserve the hand are next to those that subserve the arm, which are next to those that subserve the shoulder, and so on. This arrangement underlies the “homunculus” or a “little man” in the brain, frequently seen in neurological textbooks. Many studies in humans and animals found evidence of such order not just in the part of the brain studied by Penfield, but in all the regions of our nervous system concerned with sensing the surface of our bodies.
We propose to study how such maps arise in our brain: there are many previous studies of how neuronal maps form in the visual system or the olfactory system, but none uncover how the homunculus is formed. Our preliminary experiments show that two proteins from latrophilin and teneurin families are present as gradients, in mouse nervous system regions related with body surface sensation. Mouse mutants lacking one of these molecules are unable to accurately determine the location of a stimulus on their skin.
Here, we propose a series of experiments that will examine how latrophilins and teneurins work in the formation of brain maps, and why such maps are important for the normal function of the nervous system. One intriguing possibility is that, in addition to localizing sensory stimuli on the surface of our bodies, our brain uses these to represent our own selves versus to other individuals. This relationship between self and others has been proposed to be disrupted in neurodevelopmental disorders such as autism.
JENNIFER ESTALL
Metabolic flexibility in hepatic energy metabolism and steatotic liver disease
Summary: Our livers are responsible for storing, breaking down, and creating fuels to supply the body in times of energy demand. For example, when we fast, the liver breaks down stored fat and protein, turning them into forms of energy that can be used by other organs. To do this well, the liver listens to signals from many organs and can quickly alter its course when needs change (i.e. after we eat a meal). One way it senses these changes is by using a family of proteins called PGC-1As, which become activated when liver cells sense that other tissues need fuel. We recently found that some PGC-1A family members can also protect liver cells from damage, suggesting that these proteins have multiple important roles. Importantly, levels of PGC-1A in the liver are often low in people living with diabetes or steatotic liver disease.
Metabolic dysfunction associated steatotic liver disease (MASLD) affects about 25% of the Canadian population. The disease involves a build-up of fat in the liver that is believed to cause inflammation and permanent scarring over time. MASLD increases the risk of other diseases such as cardiovascular disease and cancer. Notably, 70-80% of people living with diabetes also have MASLD. We have shown that low PGC-1A in the liver can worsen MASLD, and our new studies are designed to reveal important role(s) for PGC-1A in controlling energy demand and responses to stress. We will also investigate whether and how disruption of these functions contributes to disease. Our project will help us better understand how the liver works, what goes wrong in MASLD, and why it is so closely linked to diabetes, in hopes of finding new ways to prevent, treat and cure these diseases.
HUA GU
Developing a vaccine enhancer to enhance pan-viral vaccination
Summary: Viral infection imposes substantial threatens to public health. Vaccination provides an effective approach for protection because it may induce high affinity antibodies to neutralize virus infection. However, current vaccination strategies have several limitations, including 1) antibody responses induced by vaccines are sometimes short-lived; 2) frequent mutations in viruses often help viruses to escape antibody protection; 3) current vaccinations cannot provide effective protection against different subtypes or variant viruses.
In these regards, there is an urgent need to develop a strategy that may induce to broadly neutralizing antibodies (bnAb) for an endured pan-viral protection. Recently, we found that ablation of transcription factor EB (TFEB) in B lymphocytes (termed the Tfeb-/- mutation) enabled mice to develop much prolonged, high titres of high affinity antibody responses relative to wild-type controls. We showed that TFEB controls the development of memory B cells (MBCs), a small group of lymphocytes that may develop into antibody-producing cells. Using influenza viruses as a model, we showed that after immunization with one subtype of viral antigen Tfeb-/- mice produce not only higher amounts of antibodies against this subtype but also other virus subtypes. This finding thus supports testing our hypothesis that targeting TFEB can be a general strategy to enhance pan vaccination.
Here, by combining the expertise of Gu Lab in immunology and Wu Lab in structure-based drug design and medicinal chemistry, we will determine whether targeting TFEB can enhance vaccination efficacy against infection of various subtype viruses. We will also elucidate molecular mechanisms by which TFEB regulates MBCs, and develop a novel chemical TFEB inhibitor to enhance pan-vaccination in humans.
This project will bring new insights into our understanding of immune responses following vaccination and identify a novel chemical agent to enhance vaccination.
MARLENE OEFFINGER (with the participation of François Robert from the IRCM) – Brigde Grant
Determining regulatory mechanisms of nucleolar and ribosomal DNA stress
Summary: Ribosomes are essential biological machines that assemble the cell’s proteins. The nucleolus is a dynamic structure in the nucleus that forms around the ribosomal (r)DNA genes that encode the large rRNA molecules that form the ribosome’s core. As cells need many ribosomes, our genome contains ~300 copies of the rDNA gene in several dense clusters, which are extensively used to produce new rRNA. Their repetitive sequences and constant use make rDNA genes particularly susceptible to potentially mutation-inducing damage.
Insufficient rDNA maintenance and repair can have profound effects on the human body, as the loss of rDNA copies and abnormal increases and decreases in ribosome generation affect organ development and have been observed in various cancers and developmental diseases. When rDNA is damaged, it is silenced to avoid generating defective ribosomes, and the nucleolus reorganizes, forming nucleolar caps that segregate the damaged rDNA and act as sites for its repair. Once repaired, the cap disappears, and the rDNA is once again used to make ribosomes.
As the rDNA genes are among the most rearranged regions in human cancer genomes, promoting their repair could be a good therapeutic strategy. However, how rDNA repair and maintenance are regulated to ensure proper ribosome generation remains unclear.
We recently identified previously unknown proteins with roles in rDNA repair. In this 5-year Project Grant, we will examine their recruitment to the nucleolar caps, protein interactions, and functions in the silencing, segregation, repair, and reactivation of rDNA in human cells. This will provide much-needed insight into how cells maintain their rDNA—and consequently, their genome—and prevent carcinogenesis, and uncover new targets for future cancer treatments.
RÉMI RABASA-LHORET (with the participation of Zekai Wu and Maha Lebbar of his research team)
Comparing Automated Insulin Delivery System PERformance (CASPER): Open-Source and Commercial AID Systems
Summary: Most people living with type 1 diabetes struggle to achieve optimal glucose targets, which can lead to devastating complications such as blindness, kidney failure, and heart disease.
The automated insulin delivery (AID) systems improve glucose management and quality of life of these individuals. These systems consist of a continuous glucose monitoring device that communicates with an insulin pump, with a software that continuously adjusts the insulin flow. Also known as artificial pancreas, these systems still require patients to make multiple adjustments: input mealtime and contents and announce physical activity. While industry developed systems are emerging, patients have simultaneously created their own systems. These open-access systems are free, easily accessible (worldwide), allow for pairing different brands of sensors and pumps, and offer extensive customization options. Although these systems are highly popular, they are not regulated by Health Canada.
This research will be the first randomized controlled trial to provide head-to-head comparison among different AID systems in adults with type 1 diabetes under free-living conditions, which provides important evidence-based data to guide the choice and optimize the use of AID systems. Participants will use two commercial systems and their open-access system, in random order, for eight weeks each. Substudies on the effectiveness of the systems with meal-related issues (e.g. various carbohydrate intake) and physical activity will be conducted.
This study involves three well-established centers in type 1 diabetes technology research: Stanford University, the University of Alberta, and the Montreal Clinical Research Institute.
MAY FARAJ (Co-Researcher in a project led by Alain Dagher at the Montreal Neurological Institute-Hospital / McGill University)
Effects of GLP-1 agonist induced weight loss on brain, metabolic, and cerebrovascular health measures
JEAN-FRANÇOIS CÔTÉ (Co-Researcher in a project led by April Rose of Lady David Institute of Jewish General Hospital / McGill University)
Exploring novel protein interactions in RAF mutant tumors to reveal new therapeutic opportunities
