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Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs

Award Number: U01HL152976
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs - Project Summary/Abstract Idiopathic pulmonary fibrosis (IPF) remains a deadly interstitial lung disease (ILD) with treatment options limited by an incomplete understanding of the mechanisms that initiate and perpetuate disease. A growing literature now implicates lung epithelial dysfunction as playing a role in the events that lead to downstream fibroblast activation, culminating in relentless fibrosis. These studies, together with the observation that lung epithelial cells in all forms of IPF display shortened telomeres, suggests that lung epithelial dysfunction may initiate IPF, and accelerated aging phenotypes or telomerase pathway abnormalities likely contribute to this pathogenesis. However, without access to patient-specific human epithelial-mesenchymal model systems, there are limited options for testing hypotheses of how epithelial changes induced by gene polymorphisms or telomerase perturbations might mechanistically contribute to IPF. Here we propose to develop a human organoid-based in vitro model system for the study of IPF. We have established a biorepository of induced pluripotent stem cells (iPSCs) generated from individuals with sporadic or familial pulmonary fibrosis. In aim 1 we apply this repository by directing the in vitro differentiation of banked IPF iPSCs carrying telomerase mutations (vs normal iPSCs) into various airway and alveolar lung epithelial cells for the purpose of generating a reductionist, epithelial-only 3D culture model of the intrinsic epithelial dysfunction that we posit may initiate pulmonary fibrosis. In aim 2 we augment the complexity of this model by introducing human organoids composed of iPSC-derived lung epithelia juxtaposed with human mesenchymal lineages in order to model the epithelial-mesenchymal interactions hypothesized to perpetuate IPF. Finally, in aim 3 we test the hypothesis that different telomerase pathway mutations result in shared lung epithelial perturbations, including short telomeres and p53 activation, that then leads to downstream mesenchymal activation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	4/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $638,086 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	4	6/24/2024	NON-COMPETING CONTINUATION	$52,088
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	4	11/21/2023	NON-COMPETING CONTINUATION	$585,998
														Subtotal = $638,086

Issue Date FY: 2023 ( Subtotal = $653,909 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	3	11/23/2022	NON-COMPETING CONTINUATION	$653,909
														Subtotal = $653,909

Issue Date FY: 2022 ( Subtotal = $675,738 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	2	11/12/2021	NON-COMPETING CONTINUATION	$608,164
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$67,574
														Subtotal = $675,738

Issue Date FY: 2021 ( Subtotal = $508,550 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Lung Diseases Research	000	1	12/14/2020	NEW	$508,550
														Subtotal = $508,550

Grand Total All Awards = $2,476,283

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Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs

Award Number: U01HL152976

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/15/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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