Novel approaches for the identification of modulators of receptor tyrosine phosphatase sigma
Notice bibliographique
Résumé
Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are type II A receptor tyrosine phosphatases which have been shown to have considerable effects on a variety of neural activities including axonal outgrowth, neural regeneration and synapse plasticity. Ligands, novel downstream adaptor, and effector proteins have been recently identified to interact with LAR-RPTPs. This association is essential for LAR-RPTPs mediated signalling. The potential therapeutic benefits for selective inhibitors of RPTPs in the treatment of CNS injury, neurodegenerative disease and memory improvement has generated recent attention. Notwithstanding, a comprehensive investigation of the regulation and signalling network controlled by RPTPs (specifically RPTPσ) is lacking.To improve our understanding how RPTPσ functions at different molecular levels, we have developed a novel cell-based system, the split luciferase RPTPσ assay. The assay is specifically designed to analyse RPTPσ activity in live cells as well as permit the screening of its relevant ligands, small molecule inhibitors and therapeutic antibodies all selected towards inhibiting RPTPσ function. Using this system, we have successfully validated known ligands such as chondroitin sulfate proteoglycans (CSPGs) and haparan sulfate proteoglycans (HSPGs) which actively control RPTPσ activity from the extracellular milieu surrounding neurons. Further, in collaboration with Dr. P. Gunning at the University of Toronto, dimeric compounds specifically targeting RPTPσ have also been shown to inhibit RPTPσ activity in vitro and in vivo. Several antibodies against the ectodomain of RPTPσ have been generated and their specificity validated with different experimental approaches. Our results further demonstrated the therapeutic potential of these RPTPσ antibodies in the treatment of spinal cord injuries and neurodegenerative diseases.In an effort to decipher the molecular mechanisms of RPTPσ functions, several interacting proteins and potential substrates have been identified by using the modified yeast-two-hybrid system. In particular, we demonstrated that p250GAP is an associate protein and a physiological relevant substrate of RPTPσ. Our results showed that the increased activity of p250GAP following RPTPσ-mediated dephosphoryaltion further attenuated Rac activity and promoted the inhibition of axonal growth.In addition to the vital role of RPTPσ in the regulation of neural activity, recent studies on RPTPσ have shown its potential activity in regulating tumorigenesis. Our results indicated that RPTPσ hinders cell growth and migration, both in vitro and in vivo. Further, we investigated the molecular mechanisms beyond the anti-tumor effects of RPTPσ. Our data demonstrated that loss of RPTPσ led to an increase in autophagy accompanied by an elevation of mitochondrial activities. These results lend support to the notion that RPTPσ suppresses cell growth and migration through its negative regulation on autophagy. In conclusion, our results have made a substantial contribution to the current understanding of the role of RPTPσ in cell growth and migration. Furthermore, the data collected in this thesis has demonstrated the importance of RPTPσ as a novel therapeutic target in a variety of human diseases.
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».