A184 DISCOVERY OF POTENTIAL LGR5 LIGANDS
Notice bibliographique
Résumé
Abstract Background LGR5, an intestinal stem cell marker, is crucial in mediating R-spondin (RSPO) signaling, supporting canonical WNT signaling for tissue development and renewal. This pathway is pivotal in gastrointestinal (GI) disease, assisting wound healing and playing a role in cancer progression and chemoresistance. While modulating the WNT pathway holds therapeutic potential, directly targeting it risks disrupting cell differentiation and organ function. LGR5, whose activity complements but does not fully overlap with the WNT pathway, represents a safer target for therapeutic intervention. Aims This study seeks to identify novel ligands for LGR5, focusing on bioactive molecules in the gut lumen and secreted soluble factors from epithelial cells. In addition, RSPO-derived peptidomimetics were designed and assessed as potential LGR5 ligands. Methods Luminal lavages from mice intestines were subjected to size-exclusion chromatography, and their activity was tested using impedance assays in HEK293 cells expressing human LGR5 (HEK293/LGR5). Active fractions were further analyzed using pull-down assays and LC-MS/MS to identify LGR5 interacting proteins. Media from cultured IECs were also processed and evaluated for potential LGR5 ligands using LC-MS/MS. Protein-protein interactions (PPIs) were confirmed via immunoprecipitation (IP). Finally, RSPO peptidomimetics based on the FU2 domain, known to bind LGR5, were tested for their ability to modulate β-catenin activity through luciferase reporter assays. Results An isoform of Urotensin II (iUTS2) from the cell culture media and three proteins from intestinal luminal extracts were identified as potential LGR5 ligands. The interaction between iUTS2 and LGR5 was confirmed through IP. As a proof of concept, six RSPO peptidomimetics were designed and tested. Although none of the peptides fully replicated RSPO1 activity, three were found to enhance the effect of RSPO1 on WNT3a-induced β-catenin activity, indicating their potential as modulators of LGR5. Conclusions This study presents the first identification of potential endogenous and peptidomimetic LGR5 ligands. Although in the preliminary stages, these findings represent a significant step toward developing selective LGR5 ligands, offering insight into LGR5 receptor functions. Such discoveries hold promise for future LGR5-targeted therapies, which could restore tissue homeostasis in conditions like inflammatory bowel disease or impede cancer progression by preventing cell adaptation and dissemination. This work was funded by a CCC-GIA research grant (2022-2025) and NSERC (RGPIN-2019-05294). Funding Agencies CCCNSERC
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».