The discovery of iPSCs provides an unprecedented opportunity for any scientist to derive an inexhaustible supply of patient-derived primary cells. These cells containing each patient's own genetic background can now be applied for in vitro human disease modeling, drug screening of personalized therapeutics, and the development of future regenerative cell-based therapies. The most valuable human clones already generated by the CTSA investigators collaborating on this proposal not only carry common disease-associated mutations and polymorphisms, but also carry knock-in fluorochrome reporters targeted to specific loci through state-of-the-art gene editing technologies. The goal of this proposal is the establishment of a CTSA network of induced pluripotent stem cell (iPSC) repositories and iPSC cores that will enable advanced disease modeling using >1000 existing normal and disease specific human cell lines and banking 6,000 additional samples procured from the 2nd and 3rd generation participants of the Framingham Study. A concerted effort for curation, sharing, and distribution of this vital resource across all CTSAs does not exist. This proposal thus creates a CTSA iPSC Network led by teams who have championed an `Open Source Biology' approach, freely sharing iPSC lines and their reprogramming reagents with more than 500 labs to date across the globe. Its goals are to make patient-derived iPSCs together with the tools and expertise for their genetic manipulation available to the greater research community on a large scale to realize their promise for extending understanding of disease and developing potential therapies. To achieve these goals, it proposes: a) national sharing of >1000 iPSC lines already derived by the CTSA teams collaborating in this proposal, representing a critical resource in high demand by both basic and clinical researchers, b) development and support of formalized education and training programs able to nationally disseminate the expertise required to fully harness these new tools and differentiate them into the wide diversity of human cell lineages, c) maintenance and sharing of open source gene-editing tools and gene edited iPSC lines that will enable CTSA investigators to manipulate the human genome at will, and d) derivation for national sharing of additional iPSC lines generated from the most densely clinically and genetically phenotyped cohort of individuals currently followed in the USA today: the ~6,000 participants of the second and third generations of the Framingham Study.

Public Health Relevance

This proposal creates a consortium of CTSAs with previously existing iPSC banks and expertise in their creation, culture, differentiation, and genetic manipulation with the goals of leveraging their collective resources and expertise to benefit the CSTA and greater research community. It further proposes the addition to the existing bank of ~2500 banked, reprogrammable blood samples from the second generation cohort of the Framingham Heart Study (FHS) as well as the additional banking of ~3700 blood samples from the Gen3 and Omni2 FHS cohorts. Together, these samples along with >1000 currently existing iPSC lines banked by participating CTSA sites will be catalogued and made available to all CTSAs along with a genome-editing ?toolbox?, consisting of already-edited iPSC lines as well protocols and reagents to allow investigators to themselves edit the genomes of lines of their choosing. Finally, CTSAs participating in this proposal will establish and conduct an annual educational, hands-on iPSC culture course to provide essential training in iPSC culture and related techniques and thus maximize the potential utility of the CTSA iPSC bank and toolbox.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01TR001810-03S1
Application #
9747426
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Brooks, Pj
Project Start
2016-09-15
Project End
2021-06-30
Budget Start
2018-09-06
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
McCauley, Katherine B; Hawkins, Finn; Kotton, Darrell N (2018) Derivation of Epithelial-Only Airway Organoids from Human Pluripotent Stem Cells. Curr Protoc Stem Cell Biol 45:e51
Reeves, Emer P; O'Dwyer, Ciara A; Dunlea, Danielle M et al. (2018) Ataluren, a New Therapeutic for Alpha-1 Antitrypsin-Deficient Individuals with Nonsense Mutations. Am J Respir Crit Care Med 198:1099-1102
Jamal, Mohamed; Lewandowski, Sara L; Lawton, Matthew L et al. (2018) Derivation and characterization of putative craniofacial mesenchymal progenitor cells from human induced pluripotent stem cells. Stem Cell Res 33:100-109
Sommer, Cesar A; Capilla, Amalia; Molina-Estevez, Francisco J et al. (2018) Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells. PLoS One 13:e0200657
Hawkins, Finn; Kramer, Philipp; Jacob, Anjali et al. (2017) Prospective isolation of NKX2-1-expressing human lung progenitors derived from pluripotent stem cells. J Clin Invest 127:2277-2294
McCauley, Katherine B; Hawkins, Finn; Serra, Maria et al. (2017) Efficient Derivation of Functional Human Airway Epithelium from Pluripotent Stem Cells via Temporal Regulation of Wnt Signaling. Cell Stem Cell 20:844-857.e6
Jacob, Anjali; Morley, Michael; Hawkins, Finn et al. (2017) Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. Cell Stem Cell 21:472-488.e10