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Regulation of Silica-induced Lung Injury by Plasminogen Activator Inhibitor-1

Award Number: R21ES032506
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Regulation of Silica-induced Lung Injury by Plasminogen Activator Inhibitor-1 - Occupational or environmental exposure to respirable crystalline silica dusts is a major cause of lung diseases worldwide. This occurs in mining, sandblasting, foundry work, agriculture, construction and more recently in oil and gas extraction, which involves hydraulic fracturing. Exposure to silica is expected to rise in the US because of mechanical handling of millions of pounds of crystalline silica (“frac sand”) used as a proppant to maintain cracks and fissures created by hydraulic fracturing of shale or rock oil deposits and processing of granites or quarts in flooring and countertops. However, the fundamental mechanisms that contribute to silicosis remains elusive. Understanding the underlying pathogenesis of silica-induced lung injury (sLI) or silica-induced pulmonary fibrosis (sPF) or silicosis could have broad implications on workers’ and public health. Increased type II alveolar epithelial cell (A2C) damage mediated by the tumor suppressor protein, p53 via upregulation of plasminogen activator inhibitor-1 (PAI-1) is strongly implicated in sLI. Further, increased expression of a pro- inflammatory cytokine; interleukin-17A (IL-17A) during sLI, augments monocyte chemotactic protein-induced protein 1 (MCPIP1). Although, multiple studies underscore the importance of IL-17A, MCPIP1 and PAI-1, and dysregulated autophagy in the pathogenesis of silicosis, there is limited information on the interrelationships between increased IL-17A, MCPIP1, PAI-1 and control of autophagy. Our proposal will address this critical gap of knowledge. We will use a range of molecular and novel interventional approaches that include the use of transgenic mice to address our working hypothesis; that IL- 17A-mediated induction of MCPIP1 and PAI-1 expression promotes aberrant autophagy; in particular mitophagy and thereby apoptosis in A2Cs, which is central to the pathogenesis of sLI and silicosis. Our objective is to establish how changes in IL-17A-induced expression of PAI-1 by MCPIP1, regulates autophagy and apoptosis in A2Cs and thereby silicosis. We will determine if targeting of this pathway with a 7-mer deletion fragment of caveolin-1 scaffolding peptide (CSP7) mitigates sLI and remodeling. Our Specific Aims are: 1) To elucidate the role of IL-17A-induced PAI-1 in the regulation of autophagy in a mouse model of sLI and determine whether silicosis can be reversed by treatment with CSP7. 2) To determine if IL17A-induced PAI-1 mediates mitophagy in mice with sLI and its mitigation by CSP7 treatment. This project will advance the field by elucidating how IL-17A mediated induction of MCPIP1, PAI-1 and autophagy reduces A2C viability, resulting in lung injury and fibrosis due to silica exposure. This proposal will expand our understanding of the pathogenesis of silicosis and test a new interventional approach to mitigate sLI and decrease its long-term morbidity.


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 = -$193,044 )
2026	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Environmental Health	000	1	2/23/2026	NEW	-$193,044
														Subtotal = -$193,044

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER	11937 US HIGHWAY 271	TYLER	TX	75708	SMITH	USA	Environmental Health	000	1	8/7/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $404,250 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT TYLER, THE	11937 US HWY 271	TYLER	TX	75708	SMITH	USA	Environmental Health	000	1	9/20/2022	NEW	$404,250
														Subtotal = $404,250

Grand Total All Awards = $211,206

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Regulation of Silica-induced Lung Injury by Plasminogen Activator Inhibitor-1

Award Number: R21ES032506

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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