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Post-Transcriptional Regulation of Lung Fibrosis.

Award Number: R01HL167010
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/05/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Post-Transcriptional Regulation of Lung Fibrosis. - PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic disease characterized with excessively deposited extracellular matrix (ECM) proteins. Persistent myofibroblast activation is considered as one of driving forces that lead to excessive ECM protein production and fibrosis in IPF. The molecular mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF have not been fully understood. KH-Type Splicing Regulatory Protein (KSRP) is a mRNA destabilizing protein involved in post-transcriptional regulation of gene expression. Preliminary data demonstrate that KSRP expression is significantly decreased in IPF lung fibroblasts and tissues when compared to that in normal human lung fibroblasts and tissues. However, the role of KSRP in lung fibrosis, and the functional consequences of pathologic KSRP downregulation in pro-fibrotic responses in IPF, are completely unknown. This proposal aims to reveal the novel restrictive role of KSRP in lung fibrosis and the molecular mechanisms involved. Preliminary data demonstrate that KSRP deficient mice have increased lung fibrosis when compared to wild-type mice in response to Bleomycin, and that KSRP deficiency promotes, while gain of KSRP inhibits, myofibroblast differentiation and ECM protein production. These data indicate that KSRP functions as a restricting factor of fibrotic reactions, and impaired KSRP function promotes fibrotic reactions and lung fibrosis. Furthermore, KSRP negatively regulates Migfilin mRNA stability and expression and KSRP deficiency results in increased Migfilin expression. Our preliminary data demonstrate that Migfilin functions as a “pro-fibrotic switch”, promoting pro-fibrotic reactions. Migfilin is required for myofibroblast differentiation and survival. Based on preliminary data, we hypothesize that KSRP functions as a restrictive regulator of lung fibrosis, and that impaired KSRP function fosters a “pro-fibrotic niche” fueling persistent myofibroblast differentiation and pro-fibrotic responses mediated by Migfilin and Migfilin mediated signaling. To test the hypothesis, three specific AIMs are proposed. Specific AIM 1 will determine the mechanisms by which KSRP regulates myofibroblast differentiation and survival. Specific AIM 2 will determine the restrictive role of KSRP in controlling ECM expression and matrix assembly. Specific AIM 3 will examine the in vivo cell-specific role of KSRP in fibrogenesis and functional consequences. The findings will help to understand the mechanisms that perpetuate persistent myofibroblast activation and pro-fibrotic responses in IPF and serve my long-term goal to develop effective therapy for IPF.


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 = $557,151 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	3	6/6/2025	NON-COMPETING CONTINUATION	$557,151
														Subtotal = $557,151

Issue Date FY: 2024 ( Subtotal = $546,008 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	001	2	6/6/2024	NON-COMPETING CONTINUATION	$546,008
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	10/12/2023	NEW	$0
														Subtotal = $546,008

Issue Date FY: 2023 ( Subtotal = $557,151 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	9/5/2023	NEW	$557,151
														Subtotal = $557,151

Grand Total All Awards = $1,660,310

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Post-Transcriptional Regulation of Lung Fibrosis.

Award Number: R01HL167010

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/05/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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