This technology combines an advanced multi-hit mouse model with integrated computational analysis to generate a highly relevant platform for therapeutic target discovery related to lung transplant complications. It employs a model that simulates the clinical conditions of donor lungs by incorporating brain death, major trauma, and hemorrhagic shock to induce diffuse alveolar damage akin to that seen in Primary Graft Dysfunction. The system uses RNA sequencing data from both mouse and human tissues along with genomic datasets such as TCGA. By analyzing cell death and inflammatory pathways, including necroptosis and apoptosis, the platform efficiently identifies potential drug targets and evaluates existing approved drugs for repurposing.
Description
The approach is differentiated by its ability to mimic complex clinical donor injuries unlike traditional ischemia-reperfusion models. The model demonstrates that healthy mouse lungs can endure extended periods of cold ischemia, thereby isolating the effects of additional clinical stresses. This unique integration of experimental design with high-throughput computational analysis enables precise mapping of regulated cell death mechanisms, setting a new standard for drug discovery and screening methods in the context of lung transplant-related complications.
Applications
- PGD treatment drug discovery
- Repurposing approved drug therapy
- Computational target identification
- Preclinical lung injury model
- RNAseq screening integration
Advantages
- Provides a clinically relevant multi-hit mouse model that closely mimics donor lung injuries in human transplant patients.
- Overcomes traditional model limitations by isolating the impact of additional clinical insults beyond cold ischemia.
- Integrates experimental and computational analyses (including RNAseq and TCGA data) to identify key regulated cell death pathways.
- Enables the discovery of novel therapeutic targets as well as the repurposing of existing drugs for Primary Graft Dysfunction.
- Supports the development of targeted screening methods for evaluating potential drug candidates.
