PROJECT SUMMARY – OVERVIEW Cystic Fibrosis results from the absence or dysfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel. Defects in CFTR are strongly associated with genetic variations in the CFTR gene that are unique to individual CF patients or to subgroups within the CF patient population. Thus, a personalized medicine approach helps customize care to individual CF patients based on the unique molecular and phenotypic characteristics associated with their CFTR gene. In this renewal application we will promote clinical, translational, and basic research collaboration to improve CF therapy and patient quality of life through personalized medicine with an emphasis to address CF minority population. This goal will be achieved through 3 integrated cores: Personalized Clinical Core, Personalized Model Systems Core and the new CF-Organ-on-a Chip Core. This will drive successful therapeutic outcomes and minimize potential adverse effects of chronic therapies. Given that the largest benefit of highly effective modulators is on lung function with little tangible effect on CF related diabetes, the focus of the CF-Organ-on-a Chip Core will be the study of mechanisms of diabetes in ductal and endocrine pancreatic cells lacking CFTR in multiple genetic mutations. We will leverage an IRB approved genotype-phenotype database available for clinical and research use, to develop Personalized Cystic Fibrosis Therapy and Research Center (PCFC) for individual patients to (i) determine his/her susceptibility to a particular form of CF mutation, and ii) take steps to mitigate the early onset of the disease. Finally, the future of CF research offers the potential for a variety of CFTR-targeted therapies (i e., CFTR modulators) to treat the underlying cause of CF, with multiple modulators currently in different stages of development.