This proposal seeks to estabalish a formalized national resource for lung researchers consisting of a lung disease-specific induced pluripotent stem cell (iPSC) bank that can be shared without restriction or exclusivity. More than 200 human lung disease-relevant iPSC clones, and their gene-edited progeny, are now banked in the Center for Regenerative Medicine (CReM) of Boston University/Boston Medical Center, providing an unprecedented opportunity for any basic scientist to derive an inexhaustible supply of patient-derived lung epithelial, vascular, immune, or interstitial cells. These cells containing each patient's own genetic background are now available for in vitro human lung disease modeling, drug screening of personalized therapeutics, and the development of future lung regeneration cell-based therapies. The most valuable human clones in this bank not only carry the most common lung disease-inducing mutations (e.g. mutations in loci encoding CFTR, Alpha-1 antitrypsin, BMPR2, SPC, SPB, ABCA3, and NKX2.1), but also carry knock-in fluorochrome reporters targeted to specific loci through state-of-the-art gene editing technologies. In parallel, the bank also includes 50 mouse iPSC clones generated from transgenic or knock-in mice that carry well characterized fluorochrome reporters of lung lineages (SPC-GFP, T1a-GFP, Tie2-GFP, SMA-GFP, and Nkx2.1-GFP). We propose to establish this cell bank through four specific aims to accomplish the goals of: a) national sharing of iPSCs that comprise a critical resource in high demand by both basic and clinical lung researchers, b) establishment of quality assurance approaches and methods for banking an exhaustive panel of human and mouse lines carrying the most common gene mutations and lung lineage reporter genes required by the majority of U.S. lung researchers in the years ahead, c) development of a formalized education and training program able to nationally disseminate the expertise required to fully harness these new tools and differentiate them into lung lineages, and d) self-sustained maintenance of the bank financially, logistically, and educationally.
Diseases affecting the lung cause considerable morbidity and mortality in the US today, yet there are few therapeutic options available due to limited access to an accessible supply of primary human lung cells for biomedical research. Induced pluripotent stem cell technologies (iPSCs) now provide easy access to cells from each individual patient, and since the cells indefinitely self-renew in the undifferentiated state they represent a inexhaustible source of patient-specific or disease-specific cells that can be expanded, frozen, shipped, and thawed in any investigators lab. This proposal makes available an expansive bank of lung disease-specific iPSC cells as a national resource available to any investigator without restriction or exclusivity. (End of Abstract)