Expanding Prognostics and Health Management (PHM) from an equipment-centric view to complex large-scale engineering systems is a challenging problem. One example for a large engineering system is the next generation national airspace system (NAS), which is a fully coupled cyber-physical-human system. This paper presents an overview of a NASA University Leadership Initiative (ULI) project which aims to address the safety needs and their technology solutions for future NAS. The ULI is a 5-year collaborative project in which researchers from several universities and commercial entities work together to advance real-time airspace safety concepts. The underlying premise is that it is imperative to be able to assess and predict the evolution of the airspace's safety state. Towards that end the work envisions to address the following issues: modeling of the airspace using both data-driven and physics-based approaches; quantifying and managing uncertainty; advancing prognostics and information fusion algorithms; and understanding and modeling human computer interface. A comprehensive simulation environment is being built that allows for assessment of performance and verification and validation. The paper discusses the various activities and places them into the context of overall NAS safety.