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Wnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILD

Award Number: R01HL134800
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project summary Systemic sclerosis (SSc) is a progressive fibrotic disease for which there is no effective treatment. Presently, the major cause of morbidity and mortality for patients with SSc is respiratory failure due to pulmonary fibrosis. Despite how commonly interstitial lung disease (ILD) occurs in SSc, it remains poorly understood and represents a major unmet medical need. The Wnt/¿-catenin (¿-cat) signaling pathway is known to be crucial for cell fate decisions throughout development and adult tissue repair after injury. Work from our group and others have shown that the Wnt/ß-cat pathway is aberrantly activated in systemic sclerosis and the associated ILD. Subsequent studies from our laboratory provided the first evidence that global genetic loss of the Wnt co-receptor Lrp5, resulting in reduced ß-cat signaling, was protective against bleomycin-induced pulmonary fibrosis and that, in the peripheral blood mononuclear cells from two independent cohorts of Idiopathic Pulmonary Fibrosis (IPF) subjects, Wnt signaling as one of the top 2 over- represented pathways associated with worsened prognosis. We have generated extensive preliminary data demonstrating that sustained ß-cat signaling in lung macrophages promotes the persistence of lung fibrosis after both bleomycin- and asbestos-induced injuries in mice, suggesting that macrophages are a key cell type through which ¿-cat signaling drives fibrosis. Our preliminary data also reveal that the alveolar macrophage population is increased in SSc-ILD lungs, where lung transcriptomes from SSc-ILD and IPF subjects share common genes. Thus, based on these findings, we reason that the signals that drive macrophage recruitment, differentiation and perdurance after tissue injury are conserved across fibrotic diseases through a common Wnt/¿-cat regulatory axis. We hypothesize that Wnt/¿-cat signaling is required for the differentiation of monocytes into recruited alveolar macrophages and that injured lung alveolar epithelium provides a contextual Wnt signal that maintains a pro-fibrotic milieu for these recruited macrophages, thus aggravating lung repair and promoting the persistence of fibrosis. We propose 1) to determine the role Wnt/ß-cat signaling to the differentiation of monocytes-macrophages in the persistence of fibrosis in SSc-ILD, 2) to determine the contribution of Wnt signaling from the injured alveolar epithelium in maintaining the pro-fibrotic macrophage phenotype in SSc-ILD, and 3) to determine the monocyte- macrophage subpopulations from subjects with SSc-ILD that express enrichment for Wnt pathway genes. We will use human blood and lung samples from subjects with SSc-ILD and complementary in vivo approaches using competitive and shielded chimeric mice, macrophage-specific transgenic mice targeting ß-cat and Wnt ligands, and chemical ablation to dissect the relative contributions of Wnt/ß-cat signaling in macrophages and epithelial cells necessary for repair after lung injury and in SSc-ILD where immune pathways are implicated.


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 = $0 )
2024	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	4	3/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	4	2/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $734,694 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	4	12/9/2020	NON-COMPETING CONTINUATION	$661,223
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$73,471
														Subtotal = $734,694

Issue Date FY: 2020 ( Subtotal = $734,694 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	3	11/27/2019	NON-COMPETING CONTINUATION	$697,959
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	001	3	1/25/2020	NON-COMPETING CONTINUATION	$36,735
														Subtotal = $734,694

Issue Date FY: 2019 ( Subtotal = $734,694 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	2	12/11/2018	NON-COMPETING CONTINUATION	$734,694
														Subtotal = $734,694

Issue Date FY: 2018 ( Subtotal = $734,694 )
2018	2018	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Lung Diseases Research	000	1	12/22/2017	NEW	$734,694
														Subtotal = $734,694

Grand Total All Awards = $2,938,776

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Wnt-beta-catenin cross interactions in alveolar macrophages and epithelial cells in persistence of SSc-ILD

Award Number: R01HL134800

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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