A75 ROLE OF LRRK2 IN INFLAMMATORY BOWEL DISEASE
Bibliographic record
Abstract
Abstract Background Variants of the leucine-rich repeat kinase 2 (LRRK2) are associated with an increased susceptibility to Parkinson disease but also Crohn’s disease (CD). Aims The present research is designed to develop a comprehensive understanding of the role of LRRK2 in immune system modulation, and how dysfunction of this pathway may lead to the development of CD. Methods WT and LRRK2-deficient neutrophil were infected with Gram-positive Bacteria (Listeria monocytogenes-LM) in a gentamicin protection assays and colony-forming unit assessment will determine the competence of LRRK2 deficient cells for bacterial phagocytosis as well as killing capacity). To examine how LRRK2 is involved in the generation of ROS during the respiratory burst, we will first examine if neutrophil from LRRK2-KO mice have altered ROS generation upon infection with LM and addition of PMA. We evaluate in vitro the ability of neutrophils from LRRK2-KO versus WT mice to transmigrate in vitro in a transwell assay using fMLP as a chemattractant. Also, we investigate the peritoneal cells (by FACS analysis) after injection of different microbial stimuli including FK105 (NOD1 ligand), MDP (NOD2 ligand) and LPS (TLR4 ligand) and anti-cd3 model of ielitis. Results We found that LRRK2 KO mice have a defect in migration of neutrophils to the peritoneal cavity after injection of different microbial stimuli including FK10565 (NOD1 ligand), MDP (NOD2 ligand) and LPS (TLR4 ligand). Neutrophils from LRRK2 mice were compromised in their ability to transmigrate in vitro in a transwell assay using fMLP as a chemoattractant. Chemotaxis was also compromised. In parallel, we designed experiments to examine reactive oxygen species (ROS) produced in response to infection of myeloid cells with bacteria. Neutrophils from LRRK2 KO mice infected with Listeria monocytogenes were less able to restrict bacteria growth compared to WT cells. Consistent with these findings, cells from LRRK2 KO mice produced lower levels of ROS following bacterial infection. In order to determine whether myeloid cell migration is compromised in vivo during inflammation, we performed experiments in WT and KO mice looking at different models of ileitis/colitis. Conclusions With this work we will further characterize the role of LRRK2 in intestinal homeostasis and mucosal barrier maintenance, including how its deficiency may predispose an individual to developing CD. Funding Agencies CAG, CIHR
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".