Wednesday, September 27, 2023 9/27/2023

Mechanoresponsive Engrailed-1-negative fibroblasts activate Engrailed-1 to promote fibrosis in wound healing

Award Number: R01GM136659
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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7. Project Summary/Abstract Adult human skin heals by developing fibrotic scar tissue, which can result in devastating disfigurement, growth restriction, and permanent functional loss. Despite a plethora of clinical options, no current treatment strategies successfully prevent or reverse this fibrotic process, and scars and their sequelae cost the United States over $20 billion every year. Progress towards the development of new therapies has been significantly hindered by a lack of understanding of the specific cell populations responsible for scarring. In 2015, our group reported that Engrailed-1 (En-1) lineage-positive fibroblasts (EPFs) are responsible for the vast majority of dorsal scar production in postnatal mice. In early fetal gestation, mice heal scarlessly via skin regeneration, an ideal outcome mediated by En-1 lineage-negative fibroblasts (ENFs; the predominant fetal fibroblast). However, it has not been established if ENFs contribute to postnatal wound healing. In this proposal, we explore for the first time the postnatal conversion of ENFs to pro-fibrotic EPFs (postnatally-derived EPFs; pEPFs) within the wound environment. First, histology, immunohistochemistry, and wounding in a novel transgenic mouse model will be used to study the conversion of ENFs to pEPFs during wound healing. By examining the behavior of ENF subpopulations (derived from papillary dermis, reticular dermis, and hypodermis) in the wound environment and confirming our findings in a tamoxifen-inducible mouse model of En-1 activation, we will precisely define the ENF population that gives rise to pro-fibrotic pEPFs. Second, we will establish the specific wound environment cues that drive ENF-to-EPF transition. Given that mechanical forces are known to modulate both scar burden and fibroblast activity, we will use in vitro and in vivo models to examine the effects of mechanical environment on En-1 activation. We will further use transcriptomic and epigenomic profiling to explore the role of mechanotransduction signaling in ENF-to-EPF transition and pEPF function. Third, having established a mechanotransduction mechanism underlying En-1 activation in wound ENFs, we will inhibit mechanotransduction signaling with the goal of blocking ENF-to-EPF transition. Specifically, we will assess whether blocking mechanotransduction results in ENF-mediated wound healing with reduced fibrosis. Our ultimate translational goal is to develop therapeutics that target fibrogenic fibroblasts to promote regenerative healing. Collectively, the proposed work will significantly enhance our understanding of the key molecular and cellular determinants of cutaneous scarring, inform the development of novel anti-scarring therapies, and shed light on the cellular origin of dermal scarring fibroblasts.


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: 2023 ( Subtotal = $317,552 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	4	2/13/2023	NON-COMPETING CONTINUATION	$31,755
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	1/17/2023	NON-COMPETING CONTINUATION	$285,797


Issue Date FY: 2022 ( Subtotal = $317,890 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	3	6/22/2022	NON-COMPETING CONTINUATION	$31,790
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	1/13/2022	NON-COMPETING CONTINUATION	$286,100


Issue Date FY: 2021 ( Subtotal = $317,427 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	001	2	2/17/2021	NON-COMPETING CONTINUATION	$31,743
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	1/29/2021	NON-COMPETING CONTINUATION	$285,684


Issue Date FY: 2020 ( Subtotal = $317,823 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	3/19/2020	NEW	$317,823


Grand Total All Awards = $1,270,692

Sum of Action Amount is $1,270,692;

Grand Total = $1,270,692

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Mechanoresponsive Engrailed-1-negative fibroblasts activate Engrailed-1 to promote fibrosis in wound healing

Award Number: R01GM136659

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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