CIHR grants: outstanding results for IRCM researchers

CIHR grants: outstanding results for IRCM researchers

The IRCM proudly celebrates the success of its researchers with the awarding of six substantial grants from the Canadian Institutes of Health Research (CIHR) for hopeful research at the IRCM. This research addresses various areas of human understanding of science, the mechanisms of which underlie several major diseases that weigh heavily on the health of Quebecers and on the health care system, such as cancer and autoimmune, neurological and degenerative diseases. Note that the success rate of IRCM researchers for this edition of the competition is 60%, surpassing the national average of about 21%. This is impressive, congratulations to all!

The selected projects and their immense potential

Dr. André Veillette's work on the role of SLAM family receptors in T cell-dependent immunity in health and disease ($908 438 grant)

T cells are critical components of the immune system for protection against microbes and cancer. Excessive activation of these cells contributes to the development of autoimmune diseases, such as diabetes and rheumatoid arthritis. The SLAM receptor family (SFRs) contains six members, as well as a few related molecules, including CD2 and CD48. SFRs play a key role in controlling the functions of T cells and other cells of the immune system and are therefore implicated in human diseases. They can also be exploited for cancer immunotherapy. Over the past 20 years, the work of Dr. Veillette's team has led to fundamental contributions in this field of scientific research. However, many crucial questions remain regarding the importance of RFSs in health, in the context of disease and as therapeutic targets. The focus of this research is to understand these important grey areas in order to improve our understanding of healthy immune regulation, the role of T cells in the context of diseases such as autoimmune disorders, as well as approaches by which T cells could be exploited for cancer immunotherapy.

Dr. Éric Lécuyer's work on the functions and underlying mechanisms of RNA localization in centrosomes ($944 775 grant)

The control of cell division is an essential process in all living organisms. Our bodies are composed of several trillion cells, all of which are formed by successive divisions of pre-existing cells from a fertilized egg. The process of cell division is an extremely complex and strictly controlled molecular machinery that has been preserved throughout evolution. When this regulation is dysfunctional, defective cell division can predispose individuals to the development of diseases such as cancer. While research on these processes has primarily focused on the role of the protein machinery in controlling cell division, this team has discovered that an entirely different class of molecules, ribonucleic acids (RNAs), can make important contributions to this regulation. Using a variety of experimental systems, including genetic studies in human cells and the fruit fly Drosophila, as well as state-of-the-art genomics and cell biology approaches, this project seeks to define the role of RNA molecules in the control of cell division. This work will reveal new regulatory mechanisms of cell division and lay the foundation for the development of RNA-directed therapies for the treatment of human diseases.

Dr. Éric Lécuyer's work on the repertoires and functional impacts of RNA-binding proteins that are sequestered by toxic RNA repeats ($818 550 grant)

Several degenerative diseases that affect the muscles and/or nervous system are caused by a similar type of genetic mutation, involving the amplification of short repeated sequences of DNA bases, called "nucleotide repeats", in the genome of affected individuals. These diseases include myotonic dystrophy type 1 (CTG repeat) or type 2 (CCTG repeat), amyotrophic lateral sclerosis/ALS (GGGCC repeat) and Huntington's disease (CAG repeat), which can be caused by recurrent expansion of repeats within specific genes. These nucleotide repeats in DNA are often converted into RNA molecules containing the corresponding repeats, which are highly toxic to the cell due to their propensity to act as molecular sponges that attract RNA-binding proteins and inactivate their normal functions. This process is thought to block many of the activities that are essential to the proper functioning of the cell and is therefore the underlying cause of the cellular degeneration observed in these diseases. This project seeks to determine whether the different types of toxic repeats present on RNA molecules have similar "sponge" properties, i.e. whether they interfere with cellular functions in similar or different ways. This work will provide crucial knowledge for the development of new therapeutic strategies.

Dr Frédéric Charron's work on a new tumor suppressor mechanism in medulloblastoma ($990 675 grant)

Medulloblastomas are the most common malignant brain tumors in children. Current treatment is non-specific and has many side effects, leaving patients with severe and permanent neurological deficits. In this context, the discovery of new therapies with fewer side effects is urgently needed. In 30% of medulloblastoma cases, there is excessive activation of a signaling pathway called the Hedgehog pathway. This pathway is required for the development and proliferation of certain cells in the cerebellum, the part of the brain where medulloblastomas form. Mutations in the Hedgehog pathway can therefore lead to the formation of medulloblastomas. One of the most common mutations occurs in the Patched gene (Ptch1). Dr. Charron's team has shown that additional mutations in other genes, combined with those in Ptch1, can increase the aggressiveness of medulloblastomas. Having identified mutations in a gene that regulates RNA quality control, which normally reduces errors in gene expression by eliminating aberrant RNAs, these researchers will test the hypothesis that down-regulation of this RNA quality control mechanism leads to increased production of proteins that drive tumor growth. This work will therefore characterize a novel tumor suppressor mechanism in medulloblastoma and will help developing new therapeutic approaches.

Dr. Frédéric Charron's work on the role of a cytoskeleton regulatory complex in commissural axon guidance ($994 500 grant)

This research program focuses on the role of Sonic hedgehog (Shh) and Netrin-1 proteins in the formation of neuronal circuits during nervous system development. Neurons generate long extensions, called axons, which move through the embryo towards their target, thanks to gradients of attraction and repulsion signals. Both Shh and Netrin-1 proteins direct axon movement by inducing physical changes in the growth cone, a mobile structure at the growing tip of axons. Our overall goal is to better understand this mechanism of axon guidance by Shh and Netrin-1. To achieve this, we will study how Shh and Netrin-1 regulate these physical changes, with particular attention to the growth cone cytoskeleton, the dynamic structure responsible for its movement and reorientation. On the cone, Shh binds to its receptor Boc and Netrin-1 binds to its receptor, DCC, to guide axons. We have identified proteins that interact, in turn, with Boc and DCC. To better understand how Shh and Netrin-1 regulate growth cone cytoskeleton remodeling, we will first assess whether these proteins that interact with Boc and DCC are essential for Shh and Netrin-1 to guide spinal cord axons and physical changes in the growth cone. Elucidation of these molecular mechanisms will lead to a better understanding of neurodevelopmental diseases involving defects in axonal guidance, such as mirror movement syndrome. 

Dr. Nicole Francis' work on the role of macromolecular organization by biomolecular condensation in the mechanism and functions of Polycomb proteins ($1 025 100 grant)

The human body consists of a multitude of cell types, organized into tissues, organs and physiological systems, whose blueprint is provided by the genome, composed of DNA. The formation and maintenance of the different cell types is made possible by maintaining some parts of the genome in an inactive state, and others in an active state, depending on the cell in question. Polycomb proteins were discovered more than 50 years ago in the fruit fly, where they play a key role in orchestrating the activation and inactivation of different parts of the genome. In humans, Polycomb proteins perform an identical function and are therefore essential for the formation of different cell types in many parts of the body, including the brain, blood and immune system. Dysfunction of the Polycomb proteins is implicated in several cancers and implicated in common diseases such as Alzheimer's disease and diabetes. The genome is packaged with various proteins in the form of chromatin, in a more or less tightly packed manner to allow or restrict the reading and use of the information it encodes. Polycomb proteins keep the inactive portions of the genome silent by tightly folding the chromatin. This work seeks to test whether Polycomb proteins exploit a process called phase separation, similar to the phenomenon by which oil forms drops in water, to concentrate in cells at certain parts of the genome and thus keep them inactive.

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