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Dissecting the role of serine metabolism in stem cell fate and tissue regeneration

Award Number: F30HD107964
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 10/01/2021
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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Dissecting the role of serine metabolism in stem cell fate and tissue regeneration - Project Summary/Abstract Tissue stem cells stem cells of the epidermis protect us from external insults, grow hair, and repair wounds. Extensive characterization of epidermal stem cells (IFE-SCs) and hair follicle stem cells (HFSCs) has uncovered how their transcriptional and signaling pathways regulate regeneration. Far less is known about how stem cells incorporate metabolic inputs, which can profoundly affect the balance between proliferation and differentiation. When regeneration is slowed in wound repair, it can be detrimental and lead to hyperproliferative states associated with inflammation and malignancy. Therefore, a knowledge of how metabolism impacts the regenerative capabilities of stem cells will fill a critical knowledge gap and an unmet and pressing need for new ways to promote tissue regeneration and wound repair. Furthermore, it may provide novel avenues to curb inflammation and metastatic cutaneous squamous cell carcinomas (SCCs). Serine is an attractive candidate for therapeutic intervention, as we know that SCC cells become addicted to serine uptake to avoid serine biosynthesis and production of the metabolite a-ketoglutarate (aKG). To be able to clinically translate these findings, we must understand how serine impacts normal HFSCs and their two regenerative processes: 1) HF regeneration, which involves lineage specification, and 2) wound healing, where HFSCs re-epithelialize epidermis and undergo a fate switch to the IFE-SC lineage. These two processes entail different stem cell fate decisions and demonstrate different responses to histone modifications. Given the importance of aKG in regulating histone modifications and its accumulation upon exogenous restriction of serine, I hypothesize that serine metabolism controls stem cell fate decisions in both wound healing and hair regeneration via aKG-dependent histone demethylase enzymes (KDMs). My preliminary data demonstrated a striking acceleration in wound repair upon dietary serine/glycine restriction, which results in increased de novo serine biosynthesis. I also observed a marked reduction in the histone mark H3K27me3, implicating activation of aKG-dependent KDMs. Thus, in Aim 1, I will first test whether dietary serine and glycine restriction controls HF regeneration. In Aim 2, I will test whether the effects of serine and glycine restriction on HF regeneration and wound repair are HFSC-autonomous. In Aim 3, I will test whether dietary ser/gly restriction alters the histone modification and chromatin accessibility landscape and dissect the underlying mechanism behind it. I expect these studies to 1) provide the first direct evidence of whether serine metabolism controls endogenous stem cells during tissue regeneration, 2) inform novel therapies to promote wound repair, and 3) enable dietary or metabolic interventions in the prevention and treatment of SCC in ways that do not harm normal regenerative processes.


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: 2026 ( Subtotal = $0 )
2026	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Child Health and Human Development Extramural Research	000	4	7/27/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Child Health and Human Development Extramural Research	001	4	6/6/2025	NON-COMPETING CONTINUATION	$564
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Child Health and Human Development Extramural Research	000	4	11/28/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $54,538

Issue Date FY: 2024 ( Subtotal = $52,694 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Child Health and Human Development Extramural Research	000	3	1/10/2024	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Child Health and Human Development Extramural Research	001	2	2/16/2023	NON-COMPETING CONTINUATION	$942
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Child Health and Human Development Extramural Research	000	2	10/18/2022	NON-COMPETING CONTINUATION	$51,752
														Subtotal = $52,694

Issue Date FY: 2021 ( Subtotal = $51,036 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Child Health and Human Development Extramural Research	001	1	9/17/2021	NEW	$0
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Child Health and Human Development Extramural Research	000	1	9/17/2021	NEW	$51,036
														Subtotal = $51,036

Grand Total All Awards = $210,962

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Dissecting the role of serine metabolism in stem cell fate and tissue regeneration

Award Number: F30HD107964

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 10/01/2021

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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