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Hypoxia-Driven NUDT21-Mediated APA Promotes Lung and Skin Fibrosis in Systemic Sclerosis

Award Number: R01AR087804
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Hypoxia-Driven NUDT21-Mediated APA Promotes Lung and Skin Fibrosis in Systemic Sclerosis - PROJECT SUMMARY ABSTRACT Systemic sclerosis (SSc) leads to fibrosis in skin and lung, and is associated with high morbidity and mortality. In addition to fibrosis, SSc has prominent vasculopathic and immune manifestations. Emerging evidence suggests that dysregulated epithelial cell differentiation and activation contribute to SSc pathogenesis by releasing profibrotic mediators. However, the underlying mechanisms remain poorly defined. We recently discovered that NUDT21 (also known as CFIm25) plays a critical role in fibrosis by regulating the expression of profibrotic mediators in epithelial cells through alternative polyadenylation (APA). NUDT21 downregulation shifts the usage of distal to proximal polyadenylation sites, causing 3' UTR shortening. Transcripts with shortened 3' UTR bypass microRNA, as well as 3'UTR binding protein-mediated suppression and generally have enhanced protein translation. Our preliminary data indicate that NUDT21 is downregulated in keratinocytes of human SSc and mouse fibrotic skin, and its downregulation leads to 3'UTR shortening of genes involved in important profibrotic pathways and enhances their protein expression. Notably, mice with keratinocyte-specific Nudt21 knockout (Nudt21f/f K5-CreERT2) or alveolar epithelial-specific Nudt21 knockout (Nudt21f/f Spc-CreERT2) develop spontaneous skin and lung fibrosis, respectively. These findings suggest a key role of epithelial NUDT21 loss in driving tissue fibrosis. Tissue hypoxia due to Raynaud's phenomenon and vasculopathy is a common, early feature of SSc and contributes to its pathogenesis. Our studies indicate that the hypoxia-inducible factor HIF1A is accumulated in SSc keratinocytes and represses epithelial NUDT21 expression through miR-181 induction. Based on these findings, we hypothesize that hypoxia/miR181- mediated NUDT21 repression in epithelial cells drives fibrosis by promoting the expression of profibrotic mediators through APA. We designed three Aims to test this hypothesis. Aim 1: Define the role of epithelial NUDT21 in murine skin and lung fibrosis models; Aim 2: Determinethe mechanisms for NUDT21 downregulation and assess their potential as therapeutic targets in skin and lung fibrosis; and Aim 3: Characterize the miR181/NUDT21/APA axis in human SSc skin. These studies are important and disease- relevant because they can elucidate a novel, epithelium-driven mechanism linking hypoxia to SSc-associated skin and lung fibrosis. The proposed research introduces several innovative approaches, including the demonstration of epithelial NUDT21 mediated post-transcriptional changes as a unifying mechanism for skin and lung fibrosis in SSc, and the investigation of hypoxia-mediated miR-181a/b induction as an upstream repressor of NUDT21. Additionally, novel models and methodologies such as Nudt21 knockout and overexpression mice, advanced bioinformatics algorithms for identifying APA profiles in single-cell RNA sequencing data, and the use of primary keratinocytes from patients with SSc are employed. Ultimately, results from these studies may facilitate the development of novel therapies for this devastating disease.


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 = $623,286 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/19/2026	NEW	$623,286
														Subtotal = $623,286

Grand Total All Awards = $623,286

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Hypoxia-Driven NUDT21-Mediated APA Promotes Lung and Skin Fibrosis in Systemic Sclerosis

Award Number: R01AR087804

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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