SUMMARY/ABSTRACT: CORE A (iPSC Gene Editing Core; iGEC) The iPSC Gene Editing Core (iGEC) will be a state-of-the-art Core Laboratory at the Boston University Chobanian & Avedisian School of Medicine that builds on the extensive experience of our investigators. The iGEC will serve the aims of Projects 1, 2, 3, and 4 through the application of state-of-the-art technical approaches to manipulating iPSC and iBC populations and generating lentiviral constructs used in each Project. The reagents that will be generated will be central to the successful completion of the individual projects composing this Program Project Grant (PPG), providing the ability to perform experiments in a significantly larger number of genetic backgrounds than would otherwise be possible. Our three specific aims are as follows. Aim 1: To edit existing iPSC and iBC lines derived from patients with genetic lung diseases to correct disease-associated variants or introduce CRISPRi or CRISPRa knock-in constructs to facilitate genetically-controlled disease modeling experiments featured in individual PPG projects. Aim 2: To perform rigorous QC testing and biobanking of edited iPSC lines generated for and utilized in all PPG projects. Aim 3: To clone, package, titer, bank, and distribute lentiviral constructs for use in PPG projects. PPG investigators have significant collective expertise in a suite of technologies, including iPSC differentiation, gene editing of iPSCs and their derivatives, and the application of lentiviruses to track cell populations, modulate gene expression, or read out pathway activation, that will be applied in Projects 1, 2, 3, and 4 of this PPG. The iGEC will centralize and standardize these innovative approaches and reagents to make them available for PPG projects. The iGEC will provide gene editing services to generate edited versions, including the introduction or correction of variants as well as the generation of knock-in constructs, of existing iPSC lines utilized in individual Projects. It will likewise clone new lentiviral constructs to facilitate the targeted knockdown or overexpression of genes of interest using CRISPRi/CRISPRa technology. It will apply rigorous QC protocols to document the provenance of edited iPSC lines through DNA “fingerprinting”, confirm their genetic stability through karyotyping, and confirm their pluripotency. Finally, it will serve as a central repository for all edited iPSCs and lentiviral constructs utilized in the PPG, applying best practices developed over time to minimize iPSC passage number and maintain the bank.