A29 INVESTIGATING THE IMPACT OF PARKINSON’S DISEASE-ASSOCIATED GENES ON INTESTINAL HOMEOSTASIS
Notice bibliographique
Résumé
Abstract Background Intestinal epithelial cells (IECs) provide an essential physical barrier between harsh luminal contents and underlying host tissue. The maintenance of intestinal homeostasis must be intricately regulated through the proliferation and differentiation of intestinal stem cells (ISCs). Dysregulation of this system results in the loss of barrier function, causing pathologies in both intestinal and extra-intestinal diseases. While Parkinson’s Disease (PD) is primarily a neurodegenerative disorder, there is increasing evidence linking PD progression and gastrointestinal (GI) dysfunction. Constipation and increased bowel permeability are often observed years prior to development of motor dysfunction in PD, and people with inflammatory bowel disease are more likely to develop PD. Our group developed a model to investigate the role of the gut in PD, demonstrating that mice with genetic ablation of the PD-associated gene Pink1 exhibited motor phenotypes only when previously infected with Gram-negative Citrobacter rodentium intestinal bacteria. As Pink1 and other PD-associated genes are expressed in IECs, we hypothesize that PD-associated gene mutations directly affect the epithelium and impact early PD pathophysiology. Aims 1. Determine how Pink1 mutation affects the transcriptional profiles in IECs at steady state and in vivo C. rodentium infection. 2. Use colonoid systems to study the effect of Pink1 mutation on epithelial activity. Methods ScRNAseq was performed on IECs isolated from uninfected and infected Pink1 WT and KO mice, sacrificed at day 7 and 14 (early and peak infection) to elucidate transcriptional differences between epithelial lineages of each genotype. Additionally, colonoids were derived from primary mouse tissue and treated with lipopolysaccharide (LPS) to determine how Pink1 KO affects the inflammatory response of the epithelium. Results Our data revealed that Pink1 KO profoundly affected several epithelial lineages. ISCs from infected Pink1 KO mice had dysregulated cell cycle genes, transit amplifying cells showed dysregulated expression of tight junction genes, and enterocytes displayed dysregulation in oxidative damage and apoptotic genes. Preliminary data from colonoids showed that Pink1 KO mice, when stimulated with LPS, had altered pro-inflammatory cytokine gene expression. We are also evaluating colon motility differences between genotypes through transit time assays, counting fecal pellets per hour, and fecal water content. Conclusions In Pink1 KO IECs, there is indeed an altered cellular response upon infection, but more information is needed to decern the mechanistic role of IECs in PD. By investigating the role of PD genes in the GI tract, these studies carry important implications for understanding the initiation and progression of PD. Funding Agencies CIHR
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 | 0,003 |
| 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 ».