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Investigating the role of Lef1 in fibroblast lineages to induce skin regeneration and reverse aging

Award Number: R01AR078743
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Investigating the role of Lef1 in fibroblast lineages to induce skin regeneration and reverse aging - PROJECT SUMMARY/ABSTRACT Understanding how to induce skin regeneration instead of scarring will have broad implications clinically and cosmetically because; they inhibit mobility, are painful, and are a source of psychological trauma. In the United States, treatment for burn victims alone amounts to $7.5 billion annually, the total market for scar treatment is estimated to be around $12 billion. A lack of understanding of the role of fibroblast heterogeneity inhibits progress in developing novel treatments for clinical conditions associated with scarring, such as, scleroderma, diabetic ulcers, psoriasis and fibrotic keloid scarring. Consequently, understanding how to regenerate skin has the potential to impact anyone who undergoes surgery, but also individuals with clinical conditions associated with scarring. Adult skin wounds heal with scars, but embryonic skin can regenerate without scarring. However, not knowing how to safely transfer the regeneration abilities of embryonic skin to adult skin remains a gap in knowledge. Thus, the long term goal of our research is to establish methods to induce fibroblasts in adult skin to have the same regenerative potential as their embryonic skin counterparts, without altering development and homeostasis. The objective of this application is to induce adult fibroblasts with embryonic transcription factors to reprogram skin to support regeneration and reverse aging. Embryonic and Neonatal skin have a transient Papillary Fibroblasts (PFs) that are lost during skin maturation and aging. Neonatal PFs reside beneath the epidermis, support skin regeneration, and express the canonical Wnt transcription factor, Lef1. A hallmark of skin aging is the degradation of PFs and the loss of Lef1 expression. Our central hypothesis is that Lef1 is the master regulator of Neonatal PF function, which induces scar-less skin regeneration and will restore PF identity in aged skin. Guided by our exciting preliminary data we will use novel transgenic mouse models and next generation sequencing technologies to investigate this hypothesis by the following specific aims: In aim 1 we will test the hypothesis that Lef1 is the master regulator of Neonatal PF function by tissue specific induction in adult skin. Here we will use wounding experiments and chamber grafting assays to test if adult scarring fibroblasts can be transformed to be regenerative. In aim 2, we will define the downstream pathways that Lef1 regulates to specify Neonatal PF functions. To do this we will perform ChIPSeq and Single-Cell-RNA-Seq with our regenerative transgenic model systems. Finally, in aim 3 we will determine if Lef1 can safely restore Neonatal PF identity and function in aged skin. We will analyze “old” transgenic mice with reprogrammed skin and test their ability to regenerate skin and inhibit “aging”. This proposal is innovative because of our novel approach of manipulating embryonic transcription factors in fibroblasts in vivo. The proposed research is significant because understanding how to safely regulate fibroblast lineages will lead to new molecular and cellular targets to regenerate organs, while also providing an important knowledge base for other clinical conditions associated with dysfunctional fibroblasts such as; psoriasis, scleroderma, and arthritis.


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 = $287,793 )
2025	2025	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/25/2025	NON-COMPETING CONTINUATION	$287,793
														Subtotal = $287,793

Issue Date FY: 2024 ( Subtotal = $310,177 )
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/27/2024	NON-COMPETING CONTINUATION	$287,793
2024	2024	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/6/2024	NON-COMPETING CONTINUATION	$22,384
														Subtotal = $310,177

Issue Date FY: 2023 ( Subtotal = $319,770 )
2023	2023	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/13/2023	NON-COMPETING CONTINUATION	$319,770
														Subtotal = $319,770

Issue Date FY: 2022 ( Subtotal = $316,572 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/16/2022	NON-COMPETING CONTINUATION	$316,572
														Subtotal = $316,572

Issue Date FY: 2021 ( Subtotal = $319,770 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/7/2021	NEW	$319,770
														Subtotal = $319,770

Grand Total All Awards = $1,554,082

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Investigating the role of Lef1 in fibroblast lineages to induce skin regeneration and reverse aging

Award Number: R01AR078743

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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