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Mechanosensing in lung fibrosis

Award Number: R01HL175067
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Mechanosensing in lung fibrosis - Project Summary Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease that results in lung scarring and breathing difficulty with a median survival of 2-5 years following diagnosis. Although the underlying mechanisms are poorly understood, fibroblastic foci develop around alveoli as dense regions of extracellular matrix (ECM) and activated fibroblasts and myofibroblasts. These stiff fibrotic lesions are implicated in the pathogenesis of IPF as poorer outcomes are observed in patients with more fibroblastic foci. Age is a major risk factor in IPF, and aging pathways, including the senescence-associated secretory pathway (SASP) and development of apoptosis- resistant fibroblasts, have been implicated in IPF. However, the interplay between ECM mechanosensing and aging in IPF remains poorly understood, and this lack of understanding limits the development of therapeutic agents. The objective of this project is to elucidate the contributions of FAK mechanosensing to ECM remodeling, senescence, apoptosis-resistance, and SASP in pulmonary fibrosis. Our central hypothesis is that aging- associated dysregulation of FAK mechanosignaling drives pulmonary fibrosis. We will exploit a novel in vitro 3D bioengineered microtissue model that mimics healthy and diseased lung tissue to dissect FAK mechanosignaling in senescent fibroblasts and an IPF-relevant aged mouse model to evaluate inhaled microparticles delivering FAK inhibitors in alleviating pulmonary fibrosis. Aim 1. Engineer microtissues using human primary fibroblasts isolated from IPF and healthy donors to model senescence and ECM remodeling in pulmonary fibrosis. Aim 2. Assess the role of FAK in regulating senescent phenotype, apoptosis, SASP, and ECM remodeling in NHLF and DHLF-IPF microtissues. Aim 3. Evaluate the therapeutic effects of inhaled microparticles delivering FAK inhibitor in modulating fibroblast senescence and alleviating pulmonary fibrosis in a bleomycin-induced lung injury model in aged mice. This research will provide new insights into cell-ECM interactions driving disease and identify therapeutic targets for the treatment of 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 = $529,398 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Lung Diseases Research	000	2	6/26/2025	NON-COMPETING CONTINUATION	$529,398
														Subtotal = $529,398

Issue Date FY: 2024 ( Subtotal = $545,400 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Lung Diseases Research	000	1	7/12/2024	NEW	$545,400
														Subtotal = $545,400

Grand Total All Awards = $1,074,798

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Mechanosensing in lung fibrosis

Award Number: R01HL175067

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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