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Reprogramming of type 2 alveolar epithelial cells in idiopathic pulmonary fibrosis and regulation by TGFb1.

Award Number: F32HL156356
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2023

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Reprogramming of type 2 alveolar epithelial cells in idiopathic pulmonary fibrosis and regulation by TGFb1. - Idiopathic Pulmonary Fibrosis (IPF) is the most common fibrotic interstitial lung disease among adults. The cause of IPF is not fully understood, and it is frequently progressive, often leading to death within several years of diagnosis. In IPF, there is loss of alveolar epithelial cells, including type 1 cells (AEC1s), which line the alveolar airspace surface, and type 2 (AEC2s), which secrete surfactant, self-renew, and give rise to AEC1s and development of honeycomb cysts. These cysts are lined by "bronchiolized" epithelium, so-called because of expression of airway and secretory cell markers such as p63, KRT5, KRT17, and MUC5B. The origin of the cells lining these cysts is not understood, but have generally been thought to be the result of migration of airway epithelial cells (basal and/or club), in a failed attempt at alveolar repair. Recent single-cell RNA (sc-RNA) sequencing studies have uncovered widespread AEC2 and other epithelial cell abnormalities in end-stage IPF tissue, such as intermediate/transitional cell states and ectopic expression of genes associated with airway cells (such as KRT5+ AEC2s). Our lab has recently shown that AEC2s are capable of reprogramming into KRT5+ basal-cell like cells in in vitro organoid cultures. These suggest a new hypothesis that the bronchiolized epithelium lining honeycomb cysts may actually be derived from reprogrammed AEC2s. This study seeks to characterize whether the epithelial abnormalities present in end-stage IPF tissue are also present earlier in the IPF disease course and to determine the role of TGFβ1 in regulating the aforementioned reprogramming. Samples from patients undergoing surgical biopsy for the purpose of clinical diagnosis will be analyzed by sc-RNA sequencing, to characterize the AEC2 and other epithelial cell populations and reconstruct estimated lineages, especially surrounding the induction of the basal-cell differentiation master- regulator Sox2 within AEC2s. These samples will be compared to normal and end-stage IPF tissue, in order to test the hypothesis that AEC2 reprogramming is an early feature of IPF. In addition, diagnostic biopsy samples will be obtained from patients who took epigallocatechin gallate (EGCG) for two weeks prior to biopsy. EGCG is a mesenchyme-specific inhibitor of TGFβ signaling under study in humans and will therefore allow us to examine the hypothesis that AEC2 reprogramming abnormalities seen in diagnostic biopsies can be reversed by TGFβ blockade. Finally, organoid co-cultures and precision-cut lung slices cultures will be used to examine the contribution of important signaling pathways, such as TGFβ, Wnt, and Notch, in driving AEC2 reprograming towards a SPC-/KRT5+ basal-cell like state. Knowledge of the mechanisms driving AEC2 reprograming in IPF may provide fundamental insight into the cause of this disorder and contribute to the development of targeted therapies for this incurable and frequently fatal disease. This proposed project will be performed as part of the research phase of Pulmonary & Critical Care Medicine Fellowship at UCSF and utilizes comprehensive institutional support and resources, in order to prepare the applicant for an independent research career.


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: 2024 ( Subtotal = -$97 )
2024	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	2	4/24/2024	SUPPLEMENT FOR EXPANSION	-$97
														Subtotal = -$97

Issue Date FY: 2023 ( Subtotal = $40,402 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	2	4/13/2023	SUPPLEMENT FOR EXPANSION	$39,275
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	002	2	7/14/2023	SUPPLEMENT FOR EXPANSION	$1,127
2023	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	4/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $40,402

Issue Date FY: 2022 ( Subtotal = $76,246 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	12/15/2021	NON-COMPETING CONTINUATION	$74,886
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	2	7/1/2022	NON-COMPETING CONTINUATION	$1,360
														Subtotal = $76,246

Issue Date FY: 2021 ( Subtotal = $72,630 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	12/15/2020	NEW	$71,430
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	002	1	4/7/2021	NEW	$0
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	1	4/7/2021	NEW	$1,200
														Subtotal = $72,630

Grand Total All Awards = $189,181

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Reprogramming of type 2 alveolar epithelial cells in idiopathic pulmonary fibrosis and regulation by TGFb1.

Award Number: F32HL156356

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2023

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