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IL-13-induced SFRP1 requires STAT3 to regulate esophageal epithelial proliferation and Basal Zone Hyperplasia in EoE

Award Number: F31DK135355
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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ABSTRACT/PROJECT SUMMARY Eosinophilic Esophagitis (EoE) is a chronic allergic disease of the esophagus clinically characterized by symptoms including difficulty swallowing, food impaction, and decreased quality of life. Histopathological features of EoE include esophageal eosinophilia (EOS/HPF) and epithelial remodeling, including dilated intercellular spaces (DIS) and basal zone hyperplasia (BZH). BZH has been linked with a fibrostenotic phenotype and clinical outcomes such as esophageal stiffness and dysfunction, food impaction and stricture [1]. The underlying immune/inflammatory responses that drive EoE pathogenesis have been extensively studied; however, studies defining the molecular basis of esophageal epithelial proliferation and BZH in EoE are sparse. Herein, we identified a critical role Secreted Frizzled-Related Protein 1 (SFRP1) in driving esophageal epithelial proliferation in EoE. A major gap in our knowledge is the molecular basis of SFRP1 regulation in Interleukin-13 (IL-13)- induced esophageal epithelial proliferation and BZH in EoE. EoE disease pathogenesis is largely driven by the cytokine IL-13, which is upregulated in esophageal biopsies of EoE patients and is sufficient to alter gene expression in esophageal epithelial cells in vitro and in vivo. In preliminary studies we show that IL-13 induces a time-dependent increase in p-STAT3 (Y705 and S727) and p-STAT6 (Y641) in esophageal epithelial cells (EPC2-ALI) and in 3D primary esophageal cell cultures; however, IL-13-induced esophageal epithelial proliferation is STAT3-dependent. Differentially expressed genes (DEGs) derived from RNAseq analyses of esophageal biopsy samples from EoE individuals and IL-13-induced EPC2-ALI cells are enrichment for genes that contain putative STAT3 binding motifs and are enriched for genes involved in epithelial proliferation and are pro-survival pathways. We identified Secreted Frizzled Related Protein 1 (SFRP1), a soluble modulator of Wnt signaling and cellular proliferation as a common STAT3 putative target and DEG in esophageal epithelial cells. We will test the central hypothesis that IL-13-STAT3-dependent regulation of esophageal epithelial proliferation is mediated by SFRP1. The specific aims (SA) will SA1) Define the requirement of STAT3 in IL-13-induced SFRP1 expression in esophageal epithelial cells and SA2) Define the role of SFRP1 in IL-13-induced esophageal epithelial cell proliferation. My long-term career goal is to become an independent investigator in an academic setting. I will be immersed in an academically rich research training environment with access to world-class facilities, equipment, and basic / clinical / translational research programs. The proposed research will be supervised by a multidisciplinary team of expert scientists and clinicians, who have the experience and expertise to mentor me and assure successful completion of the proposed studies and provide an excellent foundation training to pursue a career in medical research.


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 = $19,245 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/30/2024	NON-COMPETING CONTINUATION	$19,245
														Subtotal = $19,245

Issue Date FY: 2023 ( Subtotal = $40,515 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/15/2023	NEW	$40,515
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	2/15/2023	NEW	$0
														Subtotal = $40,515

Grand Total All Awards = $59,760

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IL-13-induced SFRP1 requires STAT3 to regulate esophageal epithelial proliferation and Basal Zone Hyperplasia in EoE

Award Number: F31DK135355

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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