UNDERSTANDING THE ROLE OF THE STROMAL CELL NICHE IN INTESTINAL STEM CELL AGING - PROJECT SUMMARY AGING COMP…

Assistance award details

Assistance award identifier

ASST_NON_R00AG076987_075

FAIN

R00AG076987

Recipient

WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$493,021

Period

Aug 1, 2023 – Jul 31, 2028

Fiscal year

2025

Place of performance state

NY

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

UNDERSTANDING THE ROLE OF THE STROMAL CELL NICHE IN INTESTINAL STEM CELL AGING - PROJECT SUMMARY AGING COMPROMISES THE NUMBERS/FUNCTION OF MAMMALIAN LGR5+ INTESTINAL STEM CELL (ISCS), WHICH DEPEND ON NICHE FACTORS PRODUCED BY NEIGHBORING CELL TYPES LIKE STROMAL CELLS. ALTHOUGH THE NECESSITY OF THESE NICHE FACTORS HAS BEEN TESTED IN VITRO, MANY UNCERTAINTIES REMAIN REGARDING THEIR IN VIVO SOURCES AND THE IMPACT OF AGING ON THEM. TO ADDRESS THESE QUESTIONS, WE HAVE FOCUSED ON RSPO3, THE DOMINANT R-SPONDIN IN THE MAMMALIAN INTESTINE AND LGR5 LIGAND THAT DRIVES ISC SELF-RENEWAL. USING NOVEL RSPO3-GFP MICE, WE HAVE DISCOVERED THAT RSPO3 IS EXPRESSED BY TWO DISTINCT POPULATIONS IN THE INTESTINAL STROMA: RSPO3+GREM1+ FIBROBLASTS (RG FIBROBLASTS) AND LYMPHATIC ENDOTHELIAL CELLS (LECS). WE HAVE ESTABLISHED HETEROTYPIC CO-CULTURE SYSTEMS OF RSPO3+ STROMAL CELLS WITH INTESTINAL EPITHELIAL ORGANOIDS, AND HAVE FOUND THAT RG FIBROBLASTS, MORE THAN LECS, SUPPORT ORGANOID GROWTH. IMPORTANTLY, THE NUMBERS/FUNCTION OF RG FIBROBLASTS DECLINE SIGNIFICANTLY IN OLD MICE. BY RNA-SEQ, WE HAVE DISCOVERED THAT S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE (AHCY), A RATE-LIMITING ENZYME IN METHIONINE METABOLISM THAT HYDROLYZES S-ADENOSYL HOMOCYSTEINE (SAH), IS THE MOST DOWNREGULATED GENE IN AGED MOUSE RG FIBROBLASTS COMPARED TO THEIR YOUNG COUNTERPARTS. FURTHERMORE, PHARMACOLOGICAL INHIBITION OF AHCY RECAPITULATES THE AGE-RELATED DECLINE IN THE ABILITY OF RG FIBROBLASTS TO SUPPORT ISCS, WHEREAS SHORT-TERM METHIONINE RESTRICTION REVERSES THE AGE-RELATED DECLINE OF RG FIBROBLASTS. WE HYPOTHESIZE THAT AHCY LOSS AND METHIONINE ACCUMULATION IN RG FIBROBLASTS ACCOUNT FOR SOME OF THE AGE-RELATED DEFICITS OF OLD ISCS THAT CAN BE REVERSED BY SHORT-TERM DIETARY METHIONINE RESTRICTION. IN THIS PROPOSAL, WE WILL TEST THE HYPOTHESIS THAT RG FIBROBLASTS ARE THE DOMINANT NICHE CELLS THAT FOSTER ISCS IN VIVO (AIM 1); THAT LOSS OF AHCY LEADS TO THE AGE-RELATED DECLINE OF RG FIBROBLASTS THROUGH ACCUMULATION OF METHIONI