Insights into new therapies for aniridia associated keratopathy in a novel mouse model
Notice bibliographique
Résumé
Aniridia is a rare genetic disorder that disrupts normal eye development. Heterozygous mutations of PAX6 are the main cause of the disease. Importantly, aniridia patients are susceptible to complete visual loss from a progressive aniridia‐associated keratopathy (AAK). The complete degeneration or disappearance of Vogt's limbal palisades is related to the more advanced stages of AAK, and therefore a limbal stem cell deficit or dysfunction (LSCD) is expected to have an important role in the development of AAK. In LSCD and aniridia, a neurotrophic deficit occurs leading to inflammation, neovascularization (CNV) consisting of blood and lymphatic vessels, and a chronic wound healing response. To establish new therapeutic options, essential knowledge is needed concerning the factors which maintain the limbal niche and how these relate to PAX6. Mouse models with aniridia often have a very aggressive phenotype, with advanced AAK observable shortly after birth, upon eye opening, despite the known delayed development of AAK in humans, occurring during the second to third decades of life. In this study, we intended to investigate more accurately the role of LSCD in progression of AAK in a new mouse model of aniridia with delayed onset of AAK using Single‐cell RNA sequencing (scRNA‐Seq) technology. This novel mouse model consists of the Pax6Sey mouse on a 129S1/SvImJ background was first developed and reported by the Simpson group in Vancouver and yields a transparent cornea at birth, and delayed development of AAK. The efficacy of new pharmacologic therapy to decrease the advancement of AAK or perhaps even stop its development can be assessed by comprehending the temporal dynamics of AAK development in this model. (scRNA‐Seq) technology is a potent tool for acquisition of essential knowledge about the characteristics and functions of LSCs, including the identification of new and highly specific expression markers and additional niche‐regulated elements that can either promote or inhibit the proliferation and differentiation of LSCs. Despite the other traditional techniques that were able to detect the average expression of genes in multiple cells, single‐cell sequencing may make it possible to detect differential signals between individual limbal stem cells. To this aim, we will compare the single cell RNA profile between Pax6 +/− haploinsufficient 129S1/SvImJ cornea vs healthy cornea from wild type mice of the same background at two different time points (at 1 month and 4 months of age). We will specifically focus on LSCs contribution to CNV pathophysiology in order to find novel therapeutic targets. The results of this study may lead to improved prevention and treatment methods for treating blindness and enhancing the clinical prognosis of people with LSCD and other LSC‐related disorders.
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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 | 0,000 | 0,001 |
| 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 | 0,000 |
| 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 ».