CFTR Lifecycle Map-A Systems Medicine Model of CFTR Maturation to Predict Possible Active Compound Combinations

Area of Science:

• Systems biology
• Molecular biology
• Genetics

Background:

• Cystic fibrosis (CF) therapeutics target CFTR but lack mutation-specific options for rare mutations.
• High-throughput screening identifies candidate compounds with unclear mechanisms of action.
• Understanding CFTR protein processing is crucial for developing effective treatments.

Purpose of the Study:

• To create a systems biology model of the CFTR maturation pathway.
• To elucidate the mechanism of action for candidate CFTR therapeutic compounds.
• To identify potential drug targets and predict synergistic effects of compound combinations.

Main Methods:

• Developed a standardized, human- and machine-readable CFTR Lifecycle Map.
• Integrated a manually curated core map (170 molecular entities, 156 reactions) from 221 publications.
• Incorporated a coarse map (1384 proteins) from large-scale interactome studies.

Main Results:

• The CFTR Lifecycle Map integrates data from diverse experimental scales.
• Identified 46 overlapping proteins between the core and coarse maps.
• The model provides a structured framework for CFTR pathway data.

Conclusions:

• The CFTR Lifecycle Map aids in identifying cellular targets for drug development.
• The model facilitates elucidation of therapeutic compound mechanisms of action.
• This systems biology approach supports hypothesis generation for novel CF therapeutics.