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CFlm25 mediated alternative polyadenylation regulates fibrosis in systemic sclerosis

Award Number: R01AR073284
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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CFlm25 mediated alternative polyadenylation regulates fibrosis in systemic sclerosis - Systemic sclerosis (SSc) is a multi-system, fibrotic disease that affects the skin and a variety of internal organs. Persistent myofibroblast activation and associated excessive extracellular matrix protein (ECMs) deposition are hallmarks of the disease. The mechanisms that account for this excessive fibrotic response remain elusive. Despite its high mortality and morbidity, there are no FDA approved medications for fibrotic complications of SSc. Our recent work indicates that a RNA-processing mechanism known as alternative polyadenylation (APA) is critical for the upregulation of profibrotic genes in dermal fibrosis through 3’ UTR tail shortening of key transcripts. Recent evidence demonstrated that a key regulator of APA is Cleavage factor Im 25 (CFIm25). The CFIm25 deletion leads to 3’ UTR shortening. A truncated 3’ UTR tail will often lack microRNA binding sites and evades the microRNA-mediated gene repression. Our preliminary data indicate CFlm25 is downregulated in fibrotic skin of SSc patients and in murine dermal fibrosis models. Knockdown of CFIm25 in normal skin fibroblasts is sufficient to promote the 3’ UTR shortening of key profibrotic genes. Moreover, the central fibrotic cytokine TGFβ suppresses CFIm25 expression through miR-203 upregulation. Overall, our data uncovered a novel mechanism by which TGFβ mediated CFIm25 downregulation leads to 3’ UTR shortening and the over-production of profibrotic factors and ECMs, and contributes to the pathogenesis of SSc. Based on this preliminary data, the main hypothesis of this project is that TGFβ and miR-203 downregulate CFIm25 in fibroblasts, resulting in dermal fibrosis by upregulation of profibrotic genes and ECMs through 3’ UTR shortening. This hypothesis will be examined in the following specific aims: Aim I: Define the fibroblast specific contribution of CFIm25 depletion in dermal fibrosis murine models. This aim will elucidate the downstream effects of CFIm25 depletion on key fibrotic pathways. Aim II: Determine the mechanisms for CFIm25 downregulation and assess their potential as therapeutic targets in dermal fibrosis. The mechanisms for TGFβ mediated miR-203 downregulation and subsequent CFIm25 repression by miR-203 will be elucidated. This aim will characterize the upstream events leading to CFIm25 depletion and will identify potential therapeutic targets. Aim III: Characterize CFIm25 in SSc human skin/fibroblasts and identify fibrotic genes dysregulated by APA. Serial dermal fibroblasts and skin samples from patients with early SSc and matched controls will be examined using a novel RNA sequencing technology. This aim will provide for the first time an unbiased, longitudinal view of CFIm25 mediated APA profile in a fibrotic disease. The proposed research links for the first time the CFIm25 mediated 3’ UTR shortening to dermal fibrosis. This can lead to discovering a key mechanism that amplifies the fibrotic response in SSc and ultimately to identifying an entirely novel target for treatment of persons with this potentially 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: 2025 ( Subtotal = -$386 )
2025	2023	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	5	11/27/2024	NON-COMPETING CONTINUATION	-$386
														Subtotal = -$386

Issue Date FY: 2023 ( Subtotal = $339,816 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/21/2023	NON-COMPETING CONTINUATION	$339,816
														Subtotal = $339,816

Issue Date FY: 2022 ( Subtotal = $336,418 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/29/2022	NON-COMPETING CONTINUATION	$336,418
														Subtotal = $336,418

Issue Date FY: 2021 ( Subtotal = $329,621 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/20/2021	NON-COMPETING CONTINUATION	$329,621
														Subtotal = $329,621

Issue Date FY: 2020 ( Subtotal = $339,816 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/24/2020	NON-COMPETING CONTINUATION	$339,816
														Subtotal = $339,816

Issue Date FY: 2019 ( Subtotal = $351,696 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	6/4/2019	NEW	$351,696
														Subtotal = $351,696

Grand Total All Awards = $1,696,981

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CFlm25 mediated alternative polyadenylation regulates fibrosis in systemic sclerosis

Award Number: R01AR073284

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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