Description du sujet de thèse

Discoidin domain receptor (DDR) 1 and 2 regulate key cellular processes and tissue homeostasis through their interaction with collagen, the most abundant protein in the human body. Dysregulation of these receptors is associated with the offset and progression of a wide range of pathologies, including kidney failure, fibrosis, cardiovascular disease, osteoarthritis and cancer. This makes DDRs extremely promising therapeutic targets. Yet, current drug candidates targeting DDR1 or DDR2 are non-specific and result in important off-target effects. In addition, DDRs remain largely understudied, and so far only binding sites common to both receptors have been identified in human collagen sequences. Consequently, selectively targeting either of them and determining their distinctive activation mechanisms has not yet been possible. In preliminary results, we have discovered that the collagen binding preferences for either DDR1 or DDR2 are regulated by electrostatic interactions. Based on this finding, we have designed triple-helical peptides (THPs) that are specific ligands for DDR2. THPs are a family of peptides that self-assemble into a triple helix structure, mimicking the conformation of collagen at the molecular level. Using THPs as ligands, we will carry out structure-activity relationships to discover DDR1-specific recognition motifs and new high affinity ligands for DDR2. The binding affinity and kinetics for each THP will be determined, enabling us to decipher the specific molecular mechanisms driving DDR1 or DDR2 attachment to collagen. We will then translate our findings to targeting DDRs in the context of disease, focusing on two pathologies that represent major clinical challenges, and for which either DDR1 or DDR2 are primary therapeutic targets. 1) DDR2 is associated with osteoarthritis (OA), a growing source of disability with over 300 million patients worldwide, where it enhances MMP activity and cartilage breakdown. 2) DDR1 expression correlates with the progression of glioblastoma (GB), the most common and aggressive type of brain cancer with a 10% survival rate 5 years post-diagnosis, where it is suspected to promote cancer cell invasion. We will use an in vitro model for OA, in which human chondrocytes are encapsulated in biomaterials functionalized with DDR2-specific THPs. Analysis of DDR activation and MMP expression will provide a direct and in-depth understanding of the involvement of DDR2 in OA at the cellular level. With this insight, we will explore the possibility of preventing OA progression using DDR2-binding THPs. The discovery of new drug candidates against OA, which represents a huge economic and social cost in Europe, will be of significant interest to the medical field. We will finally focus on blocking DDR1 activation in GB cell lines. Here, we will design high-affinity THPs that specifically bind, but do not activate, DDR1. With THPs acting as inhibitors, we will characterize the role of DDR1 in GB cell survival, proliferation and migration. This will contribute to elucidate the mechanisms behind the progression of this complex pathology. Finally, we will propose new DDR1-targeting drug candidates that can prevent GB progression and relapse, in hopes to dramatically improve both the survival rates and quality of life of patients.

Contexte de travail

This is an international collaborative project between the Laboratoire de Biologie Tissulaire et d'Ingénierie thérapeutique (Lyon, France), Imperial College London (United-Kingdom) and the University of Bayreuth (Germany). It brings together expertise in the fields of structural biology, molecular biology and tissue engineering. The job is located in the LBTI (CNRS UMR5305), at the IBCP (Institute for Biology and Chemistry of Proteins) institute in Lyon, France. The PhD candidate will have the opportunity to visit partner laboratories at Imperial College London and the University of Bayreuth during the course of their doctorate, to carry out experiments and acquire new skills. Starting date is expected to be in October 2025. The contract is for three years.

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